Quinolin-, isoquinolin-, and quinazolin-oxyalkylamides and their use as fungicides

ABSTRACT

Fungicidal compounds of the general formula (1) wherein one of X and Y is N or N-oxide and the other is CR or both of X and Y are N

This application is a 371 of International Application No.PCT/GB03/004631 filed Oct. 27, 2003, which claims priority to GB0227555.0, filed Nov. 26, 2002, the contents of which are incorporatedherein by reference.

This invention relates to novel N-alkynyl-2-quinolin-(isoquinolin- andquinazolin-)oxyalkylamides, to processes for preparing them, tocompositions containing them and to methods of using them to combatfingi, especially fungal infections of plants.

Various quinolin-8-oxyalkanecarboxylic acid derivatives are described asbeing useful as antidotes for herbicides or as herbicide safeners (see,for example, US 4,881,966, US 4,902,340 and US 5,380,852). Certainheteroaryloxy(thio)alkanoic acid amide derivatives are described in, forexample, WO 99/33810, U.S. Pat. No. 6,090,815 and JP 2001089453,together with their use as agricultural and horticultural fungicides. Inaddition, certain phenoxyalkanoic acid amide derivatives are describedin, for example, US 4,116,677 and US 4,168,319, together with their useas herbicides and mildewicides.

According to the present invention, there is provided a compound of thegeneral formula (1):

whereinone of X and Y is N or N-oxide and the other is CR or both of X and Yare N; Z is H, halo (e.g. fluoro, chloro, bromo or iodo), C₁₋₆ alkyloptionally substituted with halo or C₁₋₄ alkoxy, C₃₋₆ cycloalkyloptionally substituted with halo or C₁₋₄ alkoxy, C₂₋₄ alkenyl optionallysubstituted with halo, C₂₋₄ alkynyl optionally substituted with halo,C₁₋₆ alkoxy optionally substituted with halo or C₁₋₄ alkoxy, C₂₋₄alkenyloxy optionally substituted with halo (e.g. allyloxy), C₂₋₄alkynyloxy optionally substituted with halo (e.g. propargyloxy), cyano,nitro, C₁₋₄ alkoxycarbonyl, —OSO₂R′, S(O)_(n)R′, —COR″, —CONR″R′″,—CR″═NOR′, NR″R′″, NR″COR′, NR″CO₂R′ where n is 0, 1 or 2, R′ is C₁₋₆alkyl optionally substituted with halogen and R″ and R′″ areindependently H or C₁₋₆ alkyl or, in the case of —CONR″R′″, may join toform a 5- or 6-membered ring containing a single nitrogen atom,saturated carbon atoms and optionally a single oxygen atom;R is H, halo, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈ alkoxy, C₁₋₈ alkylthio, nitro, amino, mono- or di-(C₁₋₆)alkylamino,mono- or di-(C₂₋₆)alkenylamino, mono- or di-(C₂₋₆)alkynylamino,formylamino, C₁₋₄ alkyl(formyl)amino, C₁₋₄ alkylcarbonylamino, C₁₋₄alkoxycarbonylamino, C₁₋₄ alkyl(C₁₋₄ alkylcarbonyl)amino, cyano, formyl,C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, aminocarbonyl, mono- ordi-(C₁₋₄)alkylaminocarbonyl, carboxy, C₁₋₄ alkylcarbonyloxy,aryl(C₁₋₄)alkylcarbonyloxy, C₁₋₄ alkylsulphinyl, C₁₋₄alkylsulphonyl orC₁₋₄ alkylsulphonyloxy;R₁ is C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkyl in which the alkyl, alkenyland alkynyl groups are optionally substituted on their terminal carbonatom with one, two or three halogen atoms (e.g. 2,2,2-trifluoroethyl),with a cyano group (e.g. cyanomethyl), with a C₁₋₄ alkylcarbonyl group(e.g. acetylmethyl), with a C₁₋₄ alkoxycarbonyl group (e.g.methoxycarbonylmethyl and methoxycarbonylethyl) or with a hydroxy group(e.g. hydroxymethyl), orR₁ is alkoxyalkyl, alkylthioalkyl, alkylsulphinylalkyl oralkylsulphonylalkyl in which the total number of carbon atoms is 2 or 3(e.g. methoxymethyl, methylthiomethyl, ethoxymethyl, 2-methoxyethyl and2-methylthioethyl), orR₁ is a straight-chain C₁₋₄ alkoxy group (i.e. methoxy, ethoxy,n-propoxy and n-butoxy); R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkoxymethyl orbenzyloxymethyl in which the phenyl ring of the benzyl moiety isoptionally substituted with C₁₋₄ alkoxy;R₃ and R₄ are independently H, C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynylprovided that both are not H and that when both are other than H theircombined total of carbon atoms does not exceed 4, orR₃ and R₄ join with the carbon atom to which they are attached to form a3 or 4 membered carbocyclic ring optionally containing one O, S or Natom and optionally substituted with halo or C₁₋₄ alkyl; andR₅ is H, C₁₋₄ alkyl or C₃₋₆ cycloalkyl in which the alkyl or cycloalkylgroup is optionally substituted with halo, hydroxy, C₁₋₆ alkoxy, cyano,C₁₋₄ alkylcarbonyloxy, aminocarbonyloxy, mono- ordi(C₁₋₄)alkylaminocarbonyloxy, —S(O)_(n)(C₁₋₆)alkyl where n is 0, 1 or2, triazolyl (e.g. 1,2,4-triazol-1-yl), tri(C₁₋₄)alkylsilyloxy,optionally substituted phenoxy, optionally substituted thienyloxy,optionally substituted benzyloxy or optionally substitutedthienylmethoxy, orR₅ is optionally substituted phenyl, optionally substituted thienyl oroptionally substituted benzyl,in which the optionally substituted phenyl and thienyl rings of the R₅values are optionally substituted with one, two or three substituentsselected from halo, hydroxy, mercapto, C₁₋₄ alkyl, C₂₋₄, alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C₂₋₄ alkenyloxy, C₂₋₄ alkynyloxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, halo(C₁₋₄)alkylthio,hydroxy(C₁₋₄)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano,thiocyanato, isothiocyanato, nitro, —NR^(m)R^(n), —NHCOR^(m),NHCONR^(m)R^(n), CONR^(m)R^(n), —SO₂R^(m), —OSO₂R₇, —COR^(m),—CR^(m)═NR^(n) or —N═CR^(m)R^(n), in which R^(m) and R^(n) areindependently hydrogen, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, C₁₋₄ alkoxy,halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl, the phenyl and benzyl groupsbeing optionally substituted with halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.

The compounds of the invention contain at least one asymmetric carbonatom (and at least two when R₃ and R₄ are different) and may exist asenantiomers (or as pairs of diastereoisomers) or as mixtures of such.However, these mixtures may be separated into individual isomers orisomer pairs, and this invention embraces such isomers and mixturesthereof in all proportions. It is to be expected that for any givencompound, one isomer may be more fungicidally active than another.

Except where otherwise stated, alkyl groups and alkyl moieties ofalkoxy, alkylthio, etc., suitably contain from 1 to 4 carbon atoms inthe form of straight or branched chains. Examples are methyl, ethyl, n-and iso-propyl and n-, sec-, iso- and tert-butyl. Where alkyl moietiescontain 5 or 6 carbon atoms, examples are n-pentyl and n-hexyl.

Alkenyl and alkynyl moieties also suitable contain from 2 to 4 carbonatoms in the form of straight or branched chains. Examples are allyl,ethynyl and propargyl.

Halo includes fluoro, chloro, bromo and iodo. Most commonly it isfluoro, chloro or bromo and usually fluoro or chloro.

Of particular interest are the compounds of the general formula (1)where X is N and Y is CR (quinolines). Also of interest are thosecompounds where X and Y are both N (quinazolines) and where Y is N and Xis CR (isoquinolines).

Typically R is H, halo (for example, chloro or bromo) or cyano.

Z is typically H or halo (for example bromo).

Typically, R₁ is methyl, ethyl, n-propyl, 2,2,2-trifluoromethyl,cyanomethyl, acetylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl,hydroxymethyl, hydroxyethyl, methoxymethyl, methylthiomethyl,ethoxymethyl, 2-methoxyethyl, 2-methylthioethyl, methoxy, ethoxy,n-propoxy or n-butoxy. Ethyl is a preferred value of R₁ but also ofparticular interest are methoxy, ethoxy and methoxymethyl.

Typically R₂ is H and at least one, but preferably both of R₃ and R₄ aremethyl.

When one of R₃ and R₄ is H, the other may be methyl, ethyl or n- oriso-propyl. When one of R₃ and R₄ is methyl, the other may be H or ethylbut is preferably also methyl. R₂ also includes C₁₋₄ alkoxymethyl andbenzyloxymethyl in which the phenyl ring of the benzyl group optionallycarries an alkoxy substituent, e.g. a methoxy substituent. Such valuesof R₂ provide compounds of formula (1) that are believed to bepro-pesticidal compounds.

Typically R₅ is H, methyl, hydroxymethyl, methoxymethyl, 1-methoxyethyl,tert-butyldimethylsiloxymethyl, 3-cyanopropyl, 3-methoxypropyl,3-(1,2,4-triazol-1-yl)propyl, 3-methylthiopropyl,3-methanesulphinylpropyl or 3-methanesulphonylpropyl. Of particularinterest are compounds where R₅ is methyl, methoxymethyl or cyanopropyl.

In one aspect the invention provides a compound of the general formula(1) wherein X, Y, Z, R₁, R₂, R₃, R₄ and R₅ are as defined above exceptthat R₅ is other than H.

In another aspect, the invention provides a compound of the generalformula (1) wherein

one of X and Y is N and the other is CR or both of X and Y are N;

Z is H;

R is H, halo, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈ alkoxy, C₁₋₈ alkylthio, nitro, amino, mono- or di-(C₁₋₆)alkylamino,mono- or di-(C₂₋₆)alkenylamino, mono- or di-(C₂₋₆)alkynylamino,formylamino, C₁₋₄ alkyl(formyl)amino, C₁₋₄ alkylcarbonylamino, C₁₋₄alkyl(C₁₋₄ alkylcarbonyl)amino, cyano, formyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl, mono- or di-(C₁₋₄)alkylaminocarbonyl,carboxy, C₁₋₄ alkylcarbonyloxy, aryl(C₁₋₄)alkylcarbonyloxy, C₁₋₄alkylsulphinyl, C₁₋₄ alkylsulphonyl or C₁₋₄ alkylsulphonyloxy;R₁ is C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl in which the alkyl,alkenyl and alkynyl groups are optionally substituted on their terminalcarbon atom with one, two or three halogen atoms, with a cyano group,with a C₁₋₄ alkylcarbonyl group, with a C₁₋₄ alkoxycarbonyl group orwith a hydroxy group, orR₁ is alkoxyalkyl, alkylthioalkyl, alkylsulphinylalkyl oralkylsulphonylalkyl in which the total number of carbon atoms is 2 or 3,orR₁ is a straight-chain C₁₋₄ alkoxy group;R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkoxymethyl or benzyloxymethyl in which thephenyl ring of the benzyl moiety is optionally substituted with C₁₋₄alkoxy;R₃ and R₄ are independently H, C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynylprovided that both are not H and that when both are other than H theircombined total of carbon atoms does not exceed 4, orR₃ and R₄ join with the carbon atom to which they are attached to form a3 or 4 membered carbocyclic ring optionally containing one O, S or Natom and optionally substituted with halo or C₁₋₄ alkyl; andR₅ is H, C₁₋₄ alkyl or C₃₋₆ cycloalkyl in which the alkyl or cycloalkylgroup is optionally substituted with halo, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkylthio, cyano, C₁₋₄ alkylcarbonyloxy, aminocarbonyloxy or mono- ordi(C₁₋₄)alkylaminocarbonyloxy, tri(C₁₋₄)alkylsilyloxy, optionallysubstituted phenoxy, optionally substituted thienyloxy, optionallysubstituted benzyloxy or optionally substituted thienylmethoxy, orR₅ is optionally substituted phenyl, optionally substituted thienyl oroptionally substituted benzyl,in which the optionally substituted phenyl and thienyl rings of the R₅values are optionally substituted with one, two or three substituentsselected from halo, hydroxy, mercapto, C₁₋₄ alkyl, C₂₋₄, alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C₂₋₄ alkenyloxy, C₂₋₄ alkynyloxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, halo(C₁₋₄)alkylthio,hydroxy(C₁₋₄)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano,thiocyanato, isothiocyanato, nitro, —NR^(m)R_(n), —NHCOR^(m),—NHCONR^(m)R^(n), —CONR^(m)R^(n), —SO₂R^(m), —OSO₂R^(m), —COR^(m),—CR^(m)═NR^(n) or —N═CR^(m)R^(n), in which R^(m) and R″ areindependently hydrogen, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, C₁₋₄ alkoxy,halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl, the phenyl and benzyl groupsbeing optionally substituted with halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.

In another aspect, the invention provides a compound of the generalformula (1) wherein one of X and Y is N and the other is CR or both of Xand Y are N; Z is H; R is H, halo or cyano R₁ is methyl, ethyl,n-propyl, 2,2,2-trifluoromethyl, cyanomethyl, acetylmethyl,methoxycarbonylmethyl, methoxycarbonylethyl, hydroxymethyl,hydroxyethyl, methoxymethyl, methylthiomethyl, ethoxymethyl,2-methoxyethyl, methoxy, ethoxy, n-propoxy, n-butoxy; R₂ is H; R₃ and R₄are both methyl; and R₅ is H, methyl, hydroxymethyl, methoxymethyl,1-methoxyethyl, tert-butyldimethylsiloxymethyl, 3-cyanopropyl,3-methoxypropyl, 3-(1,2,4-triazol-1-yl)propyl, 3-methylthiopropyl,3-methanesulphinylpropyl or 3-methanesulphonylpropyl. Preferably R₁ isethyl, methoxy, ethoxy or methoxymethyl, especially ethyl. Preferably R₅is methyl, methoxymethyl or 3-cyanopropyl.

Compounds that form part of the invention are illustrated in Tables 1 to152 below.

The compounds in Table 1 are of the general formula (1) where X is N, Yis CH, Z is H, R₁ is ethyl, R₂ is H, R₃ and R are both methyl and R₅ hasthe values given in the table.

TABLE 1 Compound No. R₅ 1 H 2 CH₃ 3 C₂H₅ 4 n-C₃H₇ 5 i-C₃H₇ 6 n-C₄H₉ 7sec-C₄H₉ 8 iso-C₄H₉ 9 tert-C₄H₉ 10 HOCH₂ 11 HOC₂H₄ 12 CH₃OCH₂ 13CH₃OCH₂CH₂ 14 C₂H₅OCH₂ 15 CH₃(CH₃O)CH 16 n-C₃H₇OCH₂ 17 n-C₃H₇OC₂H₄ 18t-C₄H₉OCH₂ 19 t-C₄H₉OC₂H₄ 20 CH₃SCH₂ 21 CH₃SC₂H₄ 22 C₂H₅SCH₂ 23C₂H₅SC₂H₄ 24 n-C₃H₇SCH₂ 25 n-C₄H₉SCH₂ 26 C₆H₅OCH₂ 27 C₆H₅OC₂H₄ 284-t-C₄H₉—C₆H₄OCH₂ 29 4-F—C₆H₄OCH₂ 30 4-Cl—C₆H₄OCH₂ 31 4-CH₃—C₆H₄OCH₂ 324-Br—C₆H₄OCH₂ 33 2-F—C₆H₄OCH₂ 34 3,4-Cl₂—C₆H₃OCH₂ 35 3-CF₃—C₆H₄OCH₂ 363,5-Cl₂—C₆H₃OCH₂ 37 4-CF₃O—C₆H₅OCH₂ 38 2-CF₃—C₆H₄OCH₂ 39 4-CF₃—C₆H₄OCH₂40 2-Br—C₆H₄OCH₂ 41 2-Cl—C₆H₄OCH₂ 42 2-CH₃-4-Cl—C₆H₃OCH₂ 432-CH₃5-F—C₆H₃OCH₂ 44 3-Cl—C₆H₄OCH₂ 45 thien-2-yl-OCH₂ 46 thien-3-yl-OCH₂47 C₆H₅CH₂OCH₂ 48 thien-2-yl-CH₂OCH₂ 49 thien-3-yl-CH₂OCH₂ 50tert-C₄H₉(CH₃)₂SiOCH₂ 51 tert-C₄H₉(CH₃)₂SiOC₂H₄ 52 C₆H₅ 53 4-t-C₄H₉—C₆H₄54 4-F—C₆H₄ 55 4-Cl—C₆H₄ 56 4-CH₃—C₆H₄ 57 4-Br—C₆H₄ 58 3CH₃CO—C₆H₄ 593,4-Cl₂—C₆H₃ 60 3-CF₃—C₆H₄ 61 3,5-Cl₂—C₆H₃ 62 4-CF₃O—C₆H₄ 63 2-CF₃—C₆H₄64 4-CF₃—C₆H₄ 65 2-Br—C₆H₄ 66 2-Cl—C₆H₄ 67 2-CH₃-4-Cl—C₆H₃ 682-CH₃5-F—C₆H₃ 69 3-Cl—C₆H₄ 70 thien-2-yl 71 thien-3-yl 72 C₆H₅CH₂ 734-t-C₄H₉—C₆H₄CH₂ 74 4-F—C₆H₄CH₂ 75 4-Cl—C₆H₄CH₂ 76 4-CH₃—C₆H₄CH₂ 774-Br—C₆H₄CH₂ 78 2-F—C₆H₄CH₂ 79 3,4-Cl₂—C₆H₃CH₂ 80 3-CF₃—C₆H₄CH₂ 813,5-Cl₂—C₆H₃CH₂ 82 4-CF₃O—C₆H₅CH₂ 83 2-CF₃—C₆H₄CH₂ 84 4-CF₃—C₆H₄CH₂ 852-Br—C₆H₄CH₂ 86 2-Cl—C₆H₄CH₂ 87 2-CH₃-4-Cl—C₆H₃CH₂ 88 2-CH₃5-F—C₆H₃CH₂89 3-Cl—C₆H₄CH₂ 90 NC(CH₂)₂CH₂ 91 Cl(CH₂)₂CH₂ 92 F(CH₂)₂CH₂ 93 NCCH₂CH₂94 ClCH₂CH₂ 95 FCH₂CH₂ 96 CH₃SO(CH₂)₂CH₂ 97 CH₃SO₂(CH₂)₂CH₂ 981,2,4-triazol-1-yl-(CH₂)₂CH₂ 99 CH₃SOCH₂CH₂ 100 CH₃SO₂CH₂CH₂ 1011,2,4-triazol-1-yl-CH₂CH₂

TABLE 2

Table 2 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is methyl, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table2 is the same as compound 1 of Table 1 except that in compound 1 ofTable 2 R₁ is methyl instead of ethyl. Similarly, compounds 2 to 101 ofTable 2 are the same as compounds 2 to 101 of Table 1, respectively,except that in the compounds of Table 2 R₁ is methyl instead of ethyl.

TABLE 3

Table 3 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is n-propyl, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table3 is the same as compound 1 of Table 1 except that in compound 1 ofTable 3 R₁ is n-propyl instead of ethyl. Similarly, compounds 2 to 101of Table 3 are the same as compounds 2 to 101 of Table 1, respectively,except that in the compounds of Table 3 R₁ is n-propyl instead of ethyl.

TABLE 4

Table 4 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is 2,2,2-trifluoroethyl, R₂ is hydrogen, R₃ andP4 are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 4 is the same as compound 1 of Table 1 except thatin compound 1 of Table 4 R₁ is 2,2,2-trifluoroethyl instead of ethyl.Similarly, compounds 2 to 101 of Table 4 are the same as compounds 2 to101 of Table 1, respectively, except that in the compounds of Table 4 R₁is 2,2,2-trifluoroethyl instead of ethyl.

TABLE 5

Table 5 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is cyanomethyl, R₂ is hydrogen, R₃ and Rx areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 5 is the same as compound 1 of Table 1 except that in compound 1of Table 5 R₁ is cyanomethyl instead of ethyl. Similarly, compounds 2 to101 of Table 5 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 5 R₁ is cyanomethylinstead of ethyl.

TABLE 6

Table 6 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is acetylmethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 6 is the same as compound 1 of Table 1 except that in compound 1of Table 6 R₁ is acetylmethyl instead of ethyl. Similarly, compounds 2to 101 of Table 6 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 2 R₁ is acetylmethylinstead of ethyl.

TABLE 7

Table 7 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is methoxycarbonylmethyl, R₂ is hydrogen, R₃ andR₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 7 is the same as compound 1 of Table 1 except thatin compound 1 of Table 7 R₁ is methoxycarbonylmethyl instead of ethyl.Similarly, compounds 2 to 101 of Table 7 are the same as compounds 2 to101 of Table 1, respectively, except that in the compounds of Table 7 R₁is methoxycarbonylmethyl instead of ethyl.

TABLE 8

Table 8 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is methoxycarbonylethyl, R₂ is hydrogen, R₃ andR₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 8 is the same as compound 1 of Table 1 except thatin compound 1 of Table 8 R₁ is methoxycarbonylethyl instead of ethyl.Similarly, compounds 2 to 101 of Table 8 are the same as compounds 2 to101 of Table 1, respectively, except that in the compounds of Table 8 R₁is methoxycarbonylethyl instead of ethyl.

TABLE 9

Table 9 consists of 101 compounds of the general formula (1), where X isN, Y is CH, Z is H, R₁ is hydroxymethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 9 is the same as compound 1 of Table 1 except that in compound 1of Table 9 R₁ is hydroxymethyl instead of ethyl. Similarly, compounds 2to 101 of Table 9 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 9 R₁ ishydroxymethyl instead of ethyl.

TABLE 10

Table 10 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is hydroxethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 10 is the same as compound 1 of Table 1 except that in compound 1of Table 10 R₁ is hydroxyethyl instead of ethyl. Similarly, compounds 2to 101 of Table 10 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 10 R₁ ishydroxyethyl instead of ethyl.

TABLE 11

Table 11 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is methoxymethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 11 is the same as compound 1 of Table 1 except that in compound1 of Table 11 R₁ is methoxymethyl instead of ethyl. Similarly, compounds2 to 101 of Table 11 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 11 R₁ ismethoxymethyl instead of ethyl.

TABLE 12

Table 12 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is methylthiomethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 12 is the same as compound 1 of Table 1 except that in compound1 of Table 12 R₁ is methylthiomethyl instead of ethyl. Similarly,compounds 2 to 101 of Table 12 are the same as compounds 2 to 101 ofTable 1, respectively, except that in the compounds of Table 12 R₁ ismethylthiomethyl instead of ethyl.

TABLE 13

Table 13 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is ethoxymethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 13 is the same as compound 1 of Table 1 except that in compound 1of Table 13 R₁ is ethoxymethyl instead of ethyl. Similarly, compounds 2to 101 of Table 13 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 13 R₁ isethoxymethyl instead of ethyl.

TABLE 14

Table 14 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is 2-methoxyethyl, R₂ is hydrogen, R₃ and Rare both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 14 is the same as compound 1 of Table 1 except that in compound1 of Table 14 R₁ is 2-methoxyethyl instead of ethyl. Similarly,compounds 2 to 101 of Table 14 are the same as compounds 2 to 101 ofTable 1, respectively, except that in the compounds of Table 14 R₁ is2-methoxyethyl instead of ethyl.

TABLE 15

Table 15 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is 2-methythioethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 15 is the same as compound 1 of Table 1 except that in compound1 of Table 15 R₁ is 2-methythioethyl instead of ethyl. Similarly,compounds 2 to 101 of Table 15 are the same as compounds 2 to 101 ofTable 1, respectively, except that in the compounds of Table 15 R₁ is2-methythioethyl instead of ethyl.

TABLE 16

Table 16 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is methoxy, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table16 is the same as compound 1 of Table 1 except that in compound 1 ofTable 16 R₁ is methoxy instead of ethyl. Similarly, compounds 2 to 101of Table 16 are the same as compounds 2 to 101 of Table 1, respectively,except that in the compounds of Table 16 R₁ is methoxy instead of ethyl.

TABLE 17

Table 17 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is ethoxy, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table17 is the same as compound 1 of Table 1 except that in compound 1 ofTable 17 R₁ is ethoxy instead of ethyl. Similarly, compounds 2 to 101 ofTable 17 are the same as compounds 2 to 101 of Table 1, respectively,except that in the compounds of Table 17 R₁ is ethoxy instead of ethyl.

TABLE 18

Table 18 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is n-propoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 18 is the same as compound 1 of Table 1 except that in compound 1of Table 18 R₁ is n-propoxy instead of ethyl. Similarly, compounds 2 to101 of Table 18 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 18 R₁ is n-propoxyinstead of ethyl.

TABLE 19

Table 19 consists of 101 compounds of the general formula (1), where Xis N, Y is CH, Z is H, R₁ is n-butoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 19 is the same as compound 1 of Table 1 except that in compound 1of Table 19 R₁ is n-butoxy instead of ethyl. Similarly, compounds 2 to101 of Table 19 are the same as compounds 2 to 101 of Table 1,respectively, except that in the compounds of Table 19 R₁ is n-butoxyinstead of ethyl.

TABLE 20

Table 20 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is ethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 20 is the same as compound 1 of Table 1 except that in compound 1of Table 20 Y is N instead of CH. Similarly, compounds 2 to 101 of Table20 are the same as compounds 2 to 101 of Table 1, respectively, exceptthat in the compounds of Table 20 Y is N instead of CH.

TABLE 21

Table 21 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is methyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 21 is the same as compound 1 of Table 2 except that in compound 1of Table 21 Y is N instead of CH. Similarly, compounds 2 to 101 of Table21 are the same as compounds 2 to 101 of Table 2, respectively, exceptthat in the compounds of Table 21 Y is N instead of CH.

TABLE 22

Table 22 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is n-propyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 22 is the same as compound 1 of Table 3 except that in compound 1of Table 22 Y is N instead of CH. Similarly, compounds 2 to 101 of Table22 are the same as compounds 2 to 101 of Table 3, respectively, exceptthat in the compounds of Table 22 Y is N instead of CH.

TABLE 23

Table 23 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is 2,2,2-trifluoroethyl, R₂ is hydrogen, R₃and R are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 23 is the same as compound 1 of Table 4 except thatin compound 1 of Table 23 Y is N instead of CH. Similarly, compounds 2to 101 of Table 23 are the same as compounds 2 to 101 of Table 4,respectively, except that in the compounds of Table 23 Y is N instead ofCH.

TABLE 24

Table 24 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is cyanomethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 24 is the same as compound 1 of Table 5 except that in compound1 of Table 24 Y is N instead of CH. Similarly, compounds 2 to 101 ofTable 24 are the same as compounds 2 to 101 of Table 5, respectively,except that in the compounds of Table 24 Y is N instead of CH.

TABLE 25

Table 25 consists of 101 compounds of the general formula (1), where Xand Y are both to N, Z is H, R₁ is acetylmethyl, R₂ is hydrogen, R₃ andR₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 25 is the same as compound 1 of Table 6 except thatin compound 1 of Table 25 Y is N instead of CH. Similarly, compounds 2to 101 of Table 25 are the same as compounds 2 to 101 of Table 6,respectively, except that in the compounds of Table 25 Y is N instead ofCH.

TABLE 26

Table 26 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is methoxycarbonylmethyl, R₂ is hydrogen,R₃ and R₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 26 is the same as compound 1 of Table 7 except thatin compound 1 of Table 26 Y is N instead of CH. Similarly, compounds 2to 101 of Table 26 are the same as compounds 2 to 101 of Table 7,respectively, except that in the compounds of Table 26 Y is N instead ofCH.

TABLE 27

Table 27 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is methoxycarbonylethyl, R₂ is hydrogen, R₃and R₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 27 is the same as compound 1 of Table 8 except thatin compound 1 of Table 27 Y is N instead of CH. Similarly, compounds 2to 101 of Table 27 are the same as compounds 2 to 101 of Table 8,respectively, except that in the compounds of Table 27 Y is N instead ofCH.

TABLE 28

Table 28 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is hydroxymethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 28 is the same as compound 1 of Table 9 except that in compound1 of Table 28 Y is N instead of CH. Similarly, compounds 2 to 101 ofTable 28 are the same as compounds 2 to 101 of Table 9, respectively,except that in the compounds of Table 28 Y is N instead of CH.

TABLE 29

Table 29 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is hydroxethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 29 is the same as compound 1 of Table 10 except that incompound 1 of Table 29 Y is N instead of CH. Similarly, compounds 2 to101 of Table 29 are the same as compounds 2 to 101 of Table 10,respectively, except that in the compounds of Table 29 Y is N instead ofCH.

TABLE 30

Table 30 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is methoxymethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 30 is the same as compound 1 of Table 11 except that incompound 1 of Table 30 Y is N instead of CH. Similarly, compounds 2 to101 of Table 30 are the same as compounds 2 to 101 of Table 11,respectively, except that in the compounds of Table 30 Y is N instead ofCH.

TABLE 31

Table 31 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is methylthiomethyl, R₂ is hydrogen, R₃ andR₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 31 is the same as compound 1 of Table 12 except thatin compound 1 of Table 31 Y is N instead of CH. Similarly, compounds 2to 101 of Table 31 are the same as compounds 2 to 101 of Table 12,respectively, except that in the compounds of Table 31 Y is N instead ofCH.

TABLE 32

Table 32 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is ethoxymethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 32 is the same as compound 1 of Table 13 except that incompound 1 of Table 32 Y is N instead of CH. Similarly, compounds 2 to101 of Table 32 are the same as compounds 2 to 101 of Table 13,respectively, except that in the compounds of Table 32 Y is N instead ofCH.

TABLE 33

Table 33 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is 2-methoxyethyl, R₂ is hydrogen, R₃ andR₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 33 is the same as compound 1 of Table 14 except thatin compound 1 of Table 33 Y is N instead of CH. Similarly, compounds 2to 101 of Table 33 are the same as compounds 2 to 101 of Table 14,respectively, except that in the compounds of Table 33 Y is N instead ofCH.

TABLE 34

Table 34 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is 2-methylthioethyl, R₂ is hydrogen, R₃and R₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 34 is the same as compound 1 of Table 15 except thatin compound 1 of Table 34 Y is N instead of CH. Similarly, compounds 2to 101 of Table 34 are the same as compounds 2 to 101 of Table 15,respectively, except that in the compounds of Table 34 Y is N instead ofCH.

TABLE 35

Table 35 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is methoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 35 is the same as compound 1 of Table 16 except that in compound 1of Table 35 Y is N instead of CH. Similarly, compounds 2 to 101 of Table35 are the same as compounds 2 to 101 of Table 16, respectively, exceptthat in the compounds of Table 35 Y is N instead of CH.

TABLE 36

Table 36 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is ethoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 36 is the same as compound 1 of Table 17 except that in compound 1of Table 36 Y is N instead of CH. Similarly, compounds 2 to 101 of Table36 are the same as compounds 2 to 101 of Table 17, respectively, exceptthat in the compounds of Table 36 Y is N instead of CH.

TABLE 37

Table 37 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is n-propoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 37 is the same as compound 1 of Table 18 except that in compound 1of Table 37 Y is N instead of CH. Similarly, compounds 2 to 101 of Table37 are the same as compounds 2 to 101 of Table 18, respectively, exceptthat in the compounds of Table 37 Y is N instead of CH.

TABLE 38

Table 38 consists of 101 compounds of the general formula (1), where Xand Y are both N, Z is H, R₁ is n-butoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 38 is the same as compound 1 of Table 19 except that in compound 1of Table 38 Y is N instead of CH. Similarly, compounds 2 to 101 of Table38 are the same as compounds 2 to 101 of Table 19, respectively, exceptthat in the compounds of Table 38 Y is N instead of CH.

TABLE 39

Table 39 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is ethyl, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table39 is the same as compound 1 of Table 1 except that in compound 1 ofTable 39 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 39 are the same as compounds 2 to 101 ofTable 1, respectively, except that in the compounds of Table 39 Y is Ninstead of CH and X is CH instead of N.

TABLE 40

Table 40 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is methyl, R₂ is hydrogen, R₃ and R are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table40 is the same as compound 1 of Table 2 except that in compound 1 ofTable 40 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 40 are the same as compounds 2 to 101 ofTable 2, respectively, except that in the compounds of Table 40 Y is Ninstead of CH and X is CH instead of N.

TABLE 41

Table 41 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is n-propyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 41 is the same as compound 1 of Table 3 except that in compound 1of Table 41 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 41 are the same as compounds 2 to 101 ofTable 3, respectively, except that in the compounds of Table 41 Y is Ninstead of CH and X is CH instead of N.

TABLE 42

Table 42 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is 2,2,2-trifluoroethyl, R₂ is hydrogen, R₃and R₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 42 is the same as compound 1 of Table 4 except thatin compound 1 of Table 42 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 42 are the same as compounds 2 to101 of Table 4, respectively, except that in the compounds of Table 42 Yis N instead of CH and X is CH instead of N.

TABLE 43

Table 43 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is cyanomethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 43 is the same as compound 1 of Table 5 except that in compound 1of Table 43 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 43 are the same as compounds 2 to 101 ofTable 5, respectively, except that in the compounds of Table 43 Y is Ninstead of CH and X is CH instead of N.

TABLE 44

Table 44 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is acetylmethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 44 is the same as compound 1 of Table 6 except that in compound 1of Table 44 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 44 are the same as compounds 2 to 101 ofTable 6, respectively, except that in the compounds of Table 44 Y is Ninstead of CH and X is CH instead of N.

TABLE 45

Table 45 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is methoxycarbonylmethyl, R₂ is hydrogen, R₃and R₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 45 is the same as compound 1 of Table 7 except thatin compound 1 of Table 45 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 45 are the same as compounds 2 to101 of Table 7, respectively, except that in the compounds of Table 45 Yis N instead of CH and X is CH instead of N.

TABLE 46

Table 46 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is methoxycarbonylethyl, R₂ is hydrogen, R₃and R₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 46 is the same as compound 1 of Table 8 except thatin compound 1 of Table 46 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 46 are the same as compounds 2 to101 of Table 8, respectively, except that in the compounds of Table 46 Yis N instead of CH and X is CH instead of N.

TABLE 47

Table 47 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is hydroxymethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 47 is the same as compound 1 of Table 9 except that in compound1 of Table 47 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 47 are the same as compounds 2 to 101 ofTable 9, respectively, except that in the compounds of Table 47 Y is Ninstead of CH and X is CH instead of N.

TABLE 48

Table 48 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is hydroxethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 48 is the same as compound 1 of Table 10 except that in compound 1of Table 48 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 48 are the same as compounds 2 to 101 ofTable 10, respectively, except that in the compounds of Table 48 Y is Ninstead of CH and X is CH instead of N.

TABLE 49

Table 49 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is methoxymethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 49 is the same as compound 1 of Table 11 except that incompound 1 of Table 49 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 49 are the same as compounds 2 to101 of Table 11, respectively, except that in the compounds of Table 49Y is N instead of CH and X is CH instead of N.

TABLE 50

Table 50 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is methylthiomethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 50 is the same as compound 1 of Table 12 except that incompound 1 of Table 50 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 50 are the same as compounds 2 to101 of Table 12, respectively, except that in the compounds of Table 50Y is N instead of CH and X is CH instead of N.

TABLE 51

Table 51 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is ethoxymethyl, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 51 is the same as compound 1 of Table 13 except that in compound 1of Table 51 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 51 are the same as compounds 2 to 101 ofTable 13, respectively, except that in the compounds of Table 51 Y is Ninstead of CH and X is CH instead of N.

TABLE 52

Table 52 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is 2-methoxyethyl, R₂ is hydrogen, R₃ and R₄are both methyl and R₅ has the values listed in Table 1. Thus compound 1of Table 52 is the same as compound 1 of Table 14 except that incompound 1 of Table 52 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 52 are the same as compounds 2 to101 of Table 14, respectively, except that in the compounds of Table 52Y is N instead of CH and X is CH instead of N.

TABLE 53

Table 53 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is 2-methylthioethyl, R₂ is hydrogen, R₃ andR₄ are both methyl and R₅ has the values listed in Table 1. Thuscompound 1 of Table 53 is the same as compound 1 of Table 15 except thatin compound 1 of Table 53 Y is N instead of CH and X is CH instead of N.Similarly, compounds 2 to 101 of Table 53 are the same as compounds 2 to101 of Table 15, respectively, except that in the compounds of Table 53Y is N instead of CH and X is CH instead of N.

TABLE 54

Table 54 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is methoxy, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table54 is the same as compound 1 of Table 16 except that in compound 1 ofTable 54 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 54 are the same as compounds 2 to 101 ofTable 1, respectively, except that in the compounds of Table 16 Y is Ninstead of CH and X is CH instead of N.

TABLE 55

Table 55 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is ethoxy, R₂ is hydrogen, R₃ and R₄ are bothmethyl and R₅ has the values listed in Table 1. Thus compound 1 of Table55 is the same as compound 1 of Table 17 except that in compound 1 ofTable 55 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 55 are the same as compounds 2 to 101 ofTable 17, respectively, except that in the compounds of Table 55 Y is Ninstead of CH and X is CH instead of N.

TABLE 56

Table 56 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is n-propoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 56 is the same as compound 1 of Table 18 except that in compound 1of Table 56 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 56 are the same as compounds 2 to 101 ofTable 18, respectively, except that in the compounds of Table 56 Y is Ninstead of CH and X is CH instead of N.

TABLE 57

Table 57 consists of 101 compounds of the general formula (1), where Xis CH, Y is N, Z is H, R₁ is n-butoxy, R₂ is hydrogen, R₃ and R₄ areboth methyl and R₅ has the values listed in Table 1. Thus compound 1 ofTable 57 is the same as compound 1 of Table 19 except that in compound 1of Table 57 Y is N instead of CH and X is CH instead of N. Similarly,compounds 2 to 101 of Table 57 are the same as compounds 2 to 101 ofTable 19, respectively, except that in the compounds of Table 57 Y is Ninstead of CH and X is CH instead of N.

TABLES 58 TO 76

Tables 58 to 76 each consist of 101 compounds of the general formula (1)where X is N, Y is CCl, Z is H, R₁ is as defined in Tables 1 to 19, R₂is hydrogen, R₃ and R₄ are both methyl and R₅ has the values listed inTable 1. These tables are the same as Tables 1 to 19 (i.e. Table 58 isthe same as Table 1, Table 59 is the same as Table 2, etc.), except thatin each of Tables 58 to 76 Y is CCl instead of CH, R₁ in Tables 58 to 76has the value corresponding to its value in Tables 1 to 19, respectively(i.e. Table 58 has the same value of R₁ as Table 1, Table 59 has thesame value of R₁ as Table 2, etc.).

TABLES 77 TO 95

Tables 77 to 95 each consist of 101 compounds of the general formula (1)where X is N, Y is CBr, Z is H, R₁ is as defined in Tables 1 to 19, R₂is hydrogen, R₃ and R₄ are both methyl and R₅ has the values listed inTable 1. These tables are the same as Tables 1 to 19 (i.e. Table 77 isthe same as Table 1, Table 78 is the same as Table 2, etc.), except thatin each of Tables 77 to 95 Y is CBr instead of CH, R₁ in Tables 77 to 95has the value corresponding to its value in Tables 1 to 19, respectively(i.e. Table 77 has the same value of R₁ as Table 1, Table 78 has thesame value of R₁ as Table 2, etc.).

TABLES 96 TO 114

Tables 96 to 114 each consist of 101 compounds of the general formula(1) where X is N, Y is CCN, Z is H, R₁ is as defined in Tables 1 to 19,R₂ is hydrogen, R₃ and R are both methyl and R₅ has the values listed inTable 1. These tables are the same as Tables 1 to 19 (i.e. Table 96 isthe same as Table 1, Table 97 is the same as Table 2, etc.), except thatin each of Tables 96 to 114 Y is CCN instead of CH, R₁ in Tables 96 to114 has the value corresponding to its value in Tables 1 to 19,respectively (i.e. Table 96 has the same value of R₁ as Table 1, Table97 has the same value of R₁ as Table 2, etc.).

TABLES 115 TO 133

Tables 115 to 133 each consist of 101 compounds of the general formula(1) where X is N, Y is CBr, Z is Br, R₁ is as defined in Tables 1 to 19,R₂ is hydrogen, R₃ and R₄ are both methyl and R₅ has the values listedin Table 1. These tables are the same as Tables 1 to 19 (i.e. Table 115is the same as Table 1, Table 116 is the same as Table 2, etc.), exceptthat in each of Tables 115 to 133 Y is CBr instead of CH and Z is Brinstead of H. R₁ in Tables 115 to 133 has the value corresponding to itsvalue in Tables 1 to 19, respectively (i.e. Table 115 has the same valueof R₁ as Table 1, Table 116 has the same value of R₁ as Table 2, etc.).

TABLES 134 TO 152

Tables 134 to 152 each consist of 101 compounds of the general formula(1) where X is N-oxide, Y is CH, Z is H, R₁ is as defined in Tables 1 to19, R₂ is hydrogen, R₃ and R₄ are both methyl and R₅ has the valueslisted in Table 1. These tables are the same as Tables 1 to 19 (i.e.Table 134 is the same as Table 1, Table 135 is the same as Table 2,etc.), except that in each of Tables 134 to 152 X is the N-oxide insteadof N. R₁ in Tables 134 to 152 has the value corresponding to its valuein Tables 1 to 19, respectively (i.e. Table 134 has the same value of R₁as Table 1, Table 135 has the same value of R₁ as Table 2, etc.).

The compounds of formula (1) may be prepared as outlined in Schemes 1 to10 below in which X, Y, Z, R₁, R₂, R₃, R₄ and R₅ have the meanings givenabove, R is C₁₋₄ alkyl, R₆ is straight-chain C₁₋₄ alkyl, R₇ and R₈ areindependently H or C₁₋₄ alkyl, L is a leaving group such as a halide,for example iodide, an alkyl or aryl sulphonyloxy group, for examplemethylsulphonyloxy and tosyloxy or a triflate, Hal is halogen, R_(a) ishydrogen or C₁₋₃ alkyl, R_(b) is hydrogen or C₁₋₃ alkyl, provided thatthe total number of carbon atoms in R_(a) and R_(b) do not exceed three,R_(c) is C₁₋₆ alkyl, optionally substituted benzyl or optionallysubstituted thienylmethyl and R_(d) has the meaning ascribed to it inthe text.

As shown in Scheme 1, the compounds of general formula (1) may beprepared by reacting a compound of the general formula (2) with acompound of the general formula (3) in the presence of a base in asuitable solvent. Typical solvents include N,N-dimethylformamide andN-methylpyrrolidin-2-one. Suitable bases include potassium carbonate,sodium hydride or diisopropylethylamine.

Scheme 1

As shown in Scheme 2, compounds of the general formula (3) may beprepared by reacting an amine of the general formula (5) with an acidhalide of the general formula (4), or the corresponding acid anhydride,in the presence of a suitable inorganic or organic base, such aspotassium carbonate or diisopropylethylamine, in a solvent such asdichloromethane or tetrahydrofuran.

As shown in Scheme 3, amines of the general formula (5), wherein R₂ isH, correspond to amines of the general formula (9) and may be preparedby alkylation of a silyl-protected aminoalkyne of the general formula(7) using a suitable base, such as n-butyl lithium, followed by reactionwith a suitable alkylating reagent R₅L, such as an alkyl iodide, forexample, methyl iodide, to form an alkylated compound of the generalformula (8). In a similar procedure, a silyl-protected aminoalkyne ofthe general formula (7) may be reacted with a carbonyl derivativeR_(a)COR_(b), for example formaldehyde, using a suitable base, such asn-butyl lithium, to provide an aminoalkyne (8) containing a hydroxyalkylmoiety. The silyl protecting group may then be removed from a compoundof the general formula (8) with, for example, an aqueous acid to form anaminoalkyne of the general formula (9). Aminoalkynes of the generalformula (9) may be further derivatised, for instance when R₅ is ahydroxyalkyl group, for example, by reacting a compound of the generalformula (9) with a silylating agent (R)₃SiCl, for examplet-butyldimethylsilyl chloride, to give a derivative silylated on oxygenof the general formula (9a). In addition, a compound of the generalformula (9) may be treated with a base, such as sodium hydride orpotassium bis(trimethylsilyl)amide followed by a compound R_(c)L to givea compound of the general formula (9b). In an alternative sequence, acompound of general formula (8) may be treated with a base, such assodium or potassium bis(trimethylsilyl)amide, followed by a compoundR_(c)L, where L represents a halogen or sulphonate ester such as OSO₂Me,or OSO₂-4-tolyl, for example ethyl iodide, to give, compounds of thegeneral formula (8a), which after removal of the silyl protecting group,gives compounds of the general formula (9b).

Compounds of general formula (8), where R₅ is, for example,3-chloropropyl can be reacted with a metal cyanide salt, such as sodiumcyanide, to give compounds of general formula (8b), which can then behydrolysed, with for example an aqueous acid, to give the amines ofgeneral formula (8c). Compounds of general formula (8), where R₅ is, forexample, 3-chloropropyl can be hydrolysed, with for example an aqueousacid, to give amines of general formula (8d).

Silyl-protected aminoalkynes of the general formula (7) may be obtainedby reacting amines of general formula (6) with1,2-bis-(chlorodimethylsilyl)ethane in the presence of a suitable base,such as a tertiary organic amine base, for example, triethylamine.

Amines of the general formula (6) are either commercially available ormay be prepared by standard literature methods (see, for example,EP-A-0834498).

Alternatively, as shown in Scheme 4, compounds of the general formula(1) may be prepared by condensing a compound of the general formula(11), wherein R is H with an amine of the general formula (5) usingsuitable activating reagents such as 1-hydroxybenzotriazole andN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride.

Where R₂ is other than hydrogen, the R₂ group may be introduced into anaminoalkyne of the general formula (9) by known techniques to form anamine of the general formula (5).

Compounds of the general formula (12) may be prepared by the hydrolysisof the corresponding esters of general formula (11), wherein R_(d) isC₁₋₄ alkyl, using known techniques. The esters of the general formula(11), wherein R_(d) is C₁ alkyl and also acids of the general formula(11), wherein R_(d) is H, may be prepared by reacting a compound of thegeneral formula (2) with an ester or acid of the general formula (10a)in the presence of a suitable base, such as potassium carbonate orsodium hydride, in a suitable solvent, such as N,N-dimethylformamide.The esters or acids of the general formula (10a) are either commerciallyavailable or may be prepared by standard literature methods fromcommercially available materials.

Alternatively, as shown in Scheme 4, compounds of the general formula(11) may be prepared under Mitsunobu conditions by reacting a compoundof the general formula (2) with a compound of the general formula (10b),wherein R_(d) is C₁₋₄ alkyl, using a phosphine, such as triphenylphosphine, and an azoester, such as diethyl azodicarboxylate.

Similarly, compounds of the general formula (1) may be prepared byreacting a compound of general formula (10d) with a compound of thegeneral formula (2) under Mitsunobu conditions using a phosphine, suchas triphenyl phosphine, and an azoester, such as diethylazodicarboxylate. Compounds of general formula (10d) may be preparedfrom a compound of general formula (10c) and an amine of general formula(5) using suitable activating reagents such as 1-hydroxybenzotriazoleand N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride.Compounds (10b) and (10c) are either known compounds or may be made fromknown compounds.

In another method, the compounds of the general formula (1) may beprepared by reacting an acid halide of the general formula (13) with anamine of the general formula (5) in a suitable solvent, such asdichloromethane, in the presence of a tertiary amine, such astriethylamine, and an activating agent, such as 4-dimethylaminopyridine.

As shown in Scheme 5, an acid halide of the general formula (13) may beprepared by chlorinating a compound of the general formula (12) with asuitable chlorinating agent, such as oxalyl chloride, in a suitablesolvent, such as dichloromethane, and in the presence of, for example,N,N-dimethylformamide. The compounds of the general formula (12)correspond to the compounds of general formula (11), wherein R is H.

As shown in Scheme 6, compounds of the general formula (1), wherein R₅is H, may be reacted under Sonogashira conditions with, for example,optionally substituted phenyl or thienyl chlorides, bromides, iodides ortriflates to form substituted phenyl or thienyl compounds of generalformula (1), wherein R₅ is an optionally substituted phenyl or thienylgroup. A suitable palladium catalyst istetrakis(triphenylphosphine)palladium(0).

Compounds of the general formula (1) wherein R₅ is straight-chain C₁₋₄alkoxy, such as compounds of the general formula (14) wherein R₆ is asdefined above, may be prepared as shown in Scheme 7. Thus, esters of theformula (15) may be halogenated to give haloesters of the generalformula (16), by treatment with a suitable halogenating agent, such asN-bromosuccinimide, in a suitable solvent such as carbon tetrachloride,at between ambient temperature and the reflux temperature of thesolvent. The haloesters of the general formula (16) can be reacted withan alkali metal compound M⁺ OR₆, where M is suitably sodium or potassiumin, for example, an alcohol R₆OH as solvent, at between 0° C. and 40°C., preferably at ambient temperature, to give compounds of the generalformula (17). The esters (17) can be hydrolysed to acids of the generalformula (18), by treatment with an alkali metal hydroxide, such assodium hydroxide, in an aqueous alcohol R₆OH, at between ambienttemperature and reflux. A carboxylic acid of the general formula (18)can be condensed with an amine of the general formula (5) to give acompound of the general formula (14), where R₆ is as defined above,using suitable activating reagents such as 1-hydroxybenzotriazole andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.

Compounds of the general formula (1), wherein R₁ is C₁₋₄ alky, C₃₋₄alkenyl, C₃₋₄ alkynyl, or an alkoxyalkyl group where the total number ofcarbon atoms is 2 or 3, may be prepared as shown in Scheme 8. Thus, thesubstituted acetic acid (19) may be treated with at least twoequivalents of a base, such as lithium diisopropylamide, in a suitablesolvent such as tetrahydrofuran, at a temperature between −78° C. andambient temperature, with an alkylating agent such as RIL to givecarboxylic acids of the general formula (20) upon acidification.

As shown in Scheme 9, compounds of the general formula (1), where R₁ isa C₃₋₆ alkenyl group, may be prepared from esters of the general formula(21), wherein R₇ and R₈ are as defined above. Esters of the generalformula (21) are treated with a strong base, such as lithiumbis(trimethylsilyl)amide, at between −78° C. and ambient temperature,preferably at −78° C., and then reacted with a trialkylsilyl chloride(R)₃SiCl, such as trimethylsilyl chloride, or trialkylsilyl triflate(R)₃SiOSO₂CF₃, and allowed to warm to ambient temperature. The resultantacids of the general formula (22) obtained after hydrolysis can becondensed with amines of the general formula (5) to give the compoundsof the general formula (23), using suitable activating reagents such as1-hydroxybenzotriazole andN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride.

As shown in Scheme 10, compounds of general formula (1), where R₅ is forexample 3-chloropropyl, can be reacted with various nucleophiles such asa metal cyanide salt, for example sodium cyanide, to give compounds ofgeneral formula (24), with metal alkoxides, for example sodiummethoxide, to give compounds of general formula (25), with1,2,4-triazole in the presence of base such as triethylamine to givecompounds of general formula (26) and with metal thioalkoxides, forexample sodium methanethiolate, to give compounds of general formula(27). Compounds of general formula (27) can be treated with oxidisingagents such as sodium periodate, to give sulphoxides of general formula(28), or with oxidising agents such as 3-chloroperbenzoic acid, to givesulphones of general formula (29).

Methods for the preparation of optionally substituted hydroxyquinolinesor substituted quinolines suitable for transformation to optionallysubstituted hydroxyquinolines may be found in the literature, e.g. TheChemistry of Heterocyclic Compounds, Ed. G. Jones, John Wiley,Interscience, London and references cited therein.

For example, as shown in Scheme 11, 6-nitroquinolines optionallysubstituted in the 3 or 8 or 3 and 8 positions may be reduced to thecorresponding optionally substituted 6-aminoquinolines. Theseaminoquinolines may then be hydrolysed, for example using a strongaqueous acid such as sulphuric, phosphoric or hydrochloric acid, to thecorresponding optionally substituted 6-hydroxyquinolines.

Methods for the preparation of optionally substitutedhydroxyquinazolines or substituted quinazolines suitable fortransformation to substituted hydroxyquinazolines may be found in theliterature, e.g. The Chemistry of Heterocyclic Compounds, Ed. D. J.Brown, John Wiley, Interscience, London and references cited therein.

Other compounds of the invention may be prepared by transforming thesubstituents in the compounds of the general formula (1) using knownprocedures e.g. by the alkylation of compounds of the general formula(1), wherein R₂ is H or R₅ is H.

The compounds of formula (1) are active fungicides and may be used tocontrol one or more of the following pathogens: Pyricularia oryzae(Magnaporthe grisea) on rice and wheat and other Pyricularia spp. onother hosts; Puccinia triticina (or recondita), Puccinia striiformis andother rusts on wheat, Puccinia hordei, Puccinia striiformis and otherrusts on barley, and rusts on other hosts (for example turf, rye,coffee, pears, apples, peanuts, sugar beet, vegetables and ornamentalplants); Erysiphe cichoracearum on cucurbits (for example melon);Blumeria (or Erysiphe) graminis (powdery mildew) on barley, wheat, ryeand turf and other powdery mildews on various hosts, such asSphaerotheca macularis on hops, Sphaerotheca fusca (Sphaerothecafuliginea) on cucurbits (for example cucumber), Leveillula taurica ontomatoes, aubergine and green pepper, Podosphaera leucotricha on applesand Uncitula necator on vines; Cochliobolus spp., Helminthosporium spp.,Drechslera spp. (Pyrenophora spp.), Rhynchosporium spp., Mycosphaerellagraminicola (Septoria tritici) and Phaeosphaeria nodorum (Stagonosporanodorum or Septoria nodorum), Pseudocercosporella herpotrichoides andGaeumannomyces graminis on cereals (for example wheat, barley, rye),turf and other hosts; Cercospora arachidicola and Cercosporidiumpersonatum on peanuts and other Cercospora spp. on other hosts, forexample sugar beet, bananas, soya beans and rice; Botrytis cinerea (greymould) on tomatoes, strawberries, vegetables, vines and other hosts andother Botrytis spp. on other hosts; Alternaria spp. on vegetables (forexample carrots), oil-seed rape, apples, tomatoes, potatoes, cereals(for example wheat) and other hosts; Venturia spp. (including Venturiainaequalis (scab)) on apples, pears, stone fruit, tree nuts and otherhosts; Cladosporium spp. on a range of hosts including cereals (forexample wheat) and tomatoes; Monilinia spp. on stone fruit, tree nutsand other hosts; Didymella spp. on tomatoes, turf, wheat, cucurbits andother hosts; Phoma spp. on oil-seed rape, turf, rice, potatoes, wheatand other hosts; Aspergillus spp. and Aureobasidium spp. on wheat,lumber and other hosts; Ascochyta spp. on peas, wheat, barley and otherhosts; Stemphylium spp. (Pleospora spp.) on apples, pears, onions andother hosts; summer diseases (for example bitter rot (Glomerellacingulata), black rot or frogeye leaf spot (Botryosphaeria obtusa),Brooks fruit spot (Mycosphaerella pomi), Cedar apple rust(Gymnosporangium juniperi-virginianae), sooty blotch (Gloeodespomigena), flyspeck (Schizothyrium pomi) and white rot (Botryosphaeriadothidea)) on apples and pears; Plasmopara viticola on vines; otherdowny mildews, such as Bremia lactucae on lettuce, Peronospora spp. onsoybeans, tobacco, onions and other hosts, Pseudoperonospora humuli onhops and Pseudoperonospora cubensis on cucurbits; Pythium spp.(including Pythium ultimum) on turf and other hosts; Phytophthorainfestans on potatoes and tomatoes and other Phytophthora spp. onvegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocoaand other hosts; Thanatephorus cucumeris on rice and turf and otherRhizoctonia spp. on various hosts such as wheat and barley, peanuts,vegetables, cotton and turf; Sclerotinia spp. on turf, peanuts,potatoes, oil-seed rape and other hosts; Sclerotium spp. on turf,peanuts and other hosts; Gibberella fujikuroi on rice; Colletotrichumspp. on a range of hosts including turf, coffee and vegetables;Laetisaria fuciformis on turf; Mycosphaerella spp. on bananas, peanuts,citrus, pecans, papaya and other hosts; Diaporthe spp. on citrus,soybean, melon, pears, lupin and other hosts; Elsinoe spp. on citrus,vines, olives, pecans, roses and other hosts; Verticillium spp. on arange of hosts including hops, potatoes and tomatoes; Pyrenopeziza spp.on oil-seed rape and other hosts; Oncobasidium theobromae on cocoacausing vascular streak dieback; Fusarium spp., Typhula spp.,Microdochium nivale, Ustilago spp., Urocystis spp., Tilletia spp. andClaviceps purpurea on a variety of hosts but particularly wheat, barley,turf and maize; Ramularia spp. on sugar beet, barley and other hosts;post-harvest diseases particularly of fruit (for example Penicilliumdigitatum, Penicillium italicum and Trichoderma viride on oranges,Colletotrichum musae and Gloeosporium musarum on bananas and Botrytiscinerea on grapes); other pathogens on vines, notably Eutypa lata,Guignardia bidwellii, Phellinus igniarus, Phomopsis viticola,Pseudopeziza tracheiphila and Stereum hirsutum; other pathogens on trees(for example Lophodermium seditiosum) or lumber, notably Cephaloascusfragrans, Ceratocystis spp., Ophiostoma piceae, Penicillium spp.,Trichoderma pseudokoningii, Trichoderma viride, Trichoderma harzianum,Aspergillus niger, Leptographium lindbergi and Aureobasidium pullulans;and fungal vectors of viral diseases (for example Polymyxa graminis oncereals as the vector of barley yellow mosaic virus (BYMV) and Polymyxabetae on sugar beet as the vector of rhizomania).

The compounds of formula (I) show particularly good activity against theOomycete class of pathogens such as Phytophthora infestans, Plasmoparaspecies, e.g. Plasmopara viticola and Pythium species e.g. Pythiumultimum.

A compound of formula (1) may move acropetally, basipetally or locallyin plant tissue to be active against one or more fungi. Moreover, acompound of formula (1) may be volatile enough to be active in thevapour phase against one or more fungi on the plant.

The invention therefore provides a method of combating or controllingphytopathogenic fungi which comprises applying a fungicidally effectiveamount of a compound of formula (1), or a composition containing acompound of formula (1), to a plant, to a seed of a plant, to the locusof the plant or seed or to soil or any other plant growth medium, e.g.nutrient solution.

The term “plant” as used herein includes seedlings, bushes and trees.Furthermore, the fungicidal method of the invention includes protectant,curative, systemic, eradicant and antisporulant treatments.

The compounds of formula (1) are preferably used for agricultural,horticultural and turfgrass purposes in the form of a composition.

In order to apply a compound of formula (1) to a plant, to a seed of aplant, to the locus of the plant or seed or to soil or any other growthmedium, a compound of formula (1) is usually formulated into acomposition which includes, in addition to the compound of formula (1),a suitable inert diluent or carrier and, optionally, a surface activeagent (SFA). SFAs are chemicals which are able to modify the propertiesof an interface (for example, liquid/solid, liquid/air or liquid/liquidinterfaces) by lowering the interfacial tension and thereby leading tochanges in other properties (for example dispersion, emulsification andwetting). It is preferred that all compositions (both solid and liquidformulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to85%, for example 5 to 60%, of a compound of formula (1). The compositionis generally used for the control of fungi such that a compound offormula (1) is applied at a rate of from 0.1 g to 10 kg per hectare,preferably from 1 g to 6 kg per hectare, more preferably from 1 g to 1kg per hectare.

When used in a seed dressing, a compound of formula (1) is used at arate of 0.0001 g to 10 g (for example 0.001 g or 0.05 g), preferably0.005 g to 10 g, more preferably 0.005 g to 4 g, per kilogram of seed.

In another aspect the present invention provides a fungicidalcomposition comprising a fungicidally effective amount of a compound offormula (1) and a suitable carrier or diluent therefor.

In a still further aspect the invention provides a method of combatingand controlling fungi at a locus, which comprises treating the fungi, orthe locus of the fingi with a fungicidally effective amount of acomposition comprising a compound of formula (1).

The compositions can be chosen from a number of formulation types,including dustable powders (DP), soluble powders (SP), water solublegranules (SG), water dispersible granules (WG), wettable powders (WP),granules (GR) (slow or fast release), soluble concentrates (SL), oilmiscible liquids (OL), ultra low volume liquids (UL), emulsifiableconcentrates (EC), dispersible concentrates (DC), emulsions (both oil inwater (EW) and water in oil (EO)), micro-emulsions (ME), suspensionconcentrates (SC), aerosols, fogging/smoke formulations, capsulesuspensions (CS) and seed treatment formulations. The formulation typechosen in any instance will depend upon the particular purpose envisagedand the physical, chemical and biological properties of the compound offormula (1).

Dustable powders (DP) may be prepared by mixing a compound of formula(1) with one or more solid diluents (for example natural clays, kaolin,pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk,diatomaceous earths, calcium phosphates, calcium and magnesiumcarbonates, sulphur, lime, flours, talc and other organic and inorganicsolid carriers) and mechanically grinding the mixture to a fine powder.

Soluble powders (SP) may be prepared by mixing a compound of formula (1)with one or more water-soluble inorganic salts (such as sodiumbicarbonate, sodium carbonate or magnesium sulphate) or one or morewater-soluble organic solids (such as a polysaccharide) and, optionally,one or more wetting agents, one or more dispersing agents or a mixtureof said agents to improve water dispersibility/solubility. The mixtureis then ground to a fine powder. Similar compositions may also begranulated to form water soluble granules (SG).

Wettable powders (WP) may be prepared by mixing a compound of formula(1) with one or more solid diluents or carriers, one or more wettingagents and, preferably, one or more dispersing agents and, optionally,one or more suspending agents to facilitate the dispersion in liquids.The mixture is then ground to a fine powder. Similar compositions mayalso be granulated to form water dispersible granules (WG).

Granules (GR) may be formed either by granulating a mixture of acompound of formula (1) and one or more powdered solid diluents orcarriers, or from pre-formed blank granules by absorbing a compound offormula (1) (or a solution thereof, in a suitable agent) in a porousgranular material (such as pumice, attapulgite clays, fuller's earth,kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing acompound of formula (1) (or a solution thereof, in a suitable agent) onto a hard core material (such as sands, silicates, mineral carbonates,sulphates or phosphates) and drying if necessary. Agents which arecommonly used to aid absorption or adsorption include solvents (such asaliphatic and aromatic petroleum solvents, alcohols, ethers, ketones andesters) and sticking agents (such as polyvinyl acetates, polyvinylalcohols, dextrins, sugars and vegetable oils). One or more otheradditives may also be included in granules (for example an emulsifyingagent, wetting agent or dispersing agent).

Dispersible Concentrates (DC) may be prepared by dissolving a compoundof formula (1) in water or an organic solvent, such as a ketone, alcoholor glycol ether. These solutions may contain a surface active agent (forexample to improve water dilution or prevent crystallisation in a spraytank).

Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may beprepared by dissolving a compound of formula (1) in an organic solvent(optionally containing one or more wetting agents, one or moreemulsifying agents or a mixture of said agents). Suitable organicsolvents for use in ECs include aromatic hydrocarbons (such asalkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100,SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark),ketones (such as cyclohexanone or methylcyclohexanone), alcohols (suchas benzyl alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones(such as N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides offatty acids (such as C₈–C₁₀ fatty acid dimethylamide) and chlorinatedhydrocarbons. An EC product may spontaneously emulsify on addition towater, to produce an emulsion with sufficient stability to allow sprayapplication through appropriate equipment. Preparation of an EW involvesobtaining a compound of formula (1) either as a liquid (if it is not aliquid at room temperature, it may be melted at a reasonabletemperature, typically below 70° C.) or in solution (by dissolving it inan appropriate solvent) and then emulsifying the resultant liquid orsolution into water containing one or more SFAs, under high shear, toproduce an emulsion. Suitable solvents for use in EWs include vegetableoils, chlorinated hydrocarbons (such as chlorobenzenes), aromaticsolvents (such as alkylbenzenes or alkylnaphthalenes) and otherappropriate organic solvents which have a low solubility in water.

Microemulsions (Ma) may be prepared by mixing water with a blend of oneor more solvents with one or more SFAs, to produce spontaneously athermodynamically stable isotropic liquid formulation. A compound offormula (1) is present initially in either the water or the solvent/SFAblend. Suitable solvents for use in MEs include those hereinbeforedescribed for use in in ECs or in EWs. An ME may be either anoil-in-water or a water-in-oil system (which system is present may bedetermined by conductivity measurements) and may be suitable for mixingwater-soluble and oil-soluble pesticides in the same formulation. An MEis suitable for dilution into water, either remaining as a microemulsionor forming a conventional oil-in-water emulsion.

Suspension concentrates (SC) may comprise aqueous or non-aqueoussuspensions of finely divided insoluble solid particles of a compound offormula (1). SCs may be prepared by ball or bead milling the solidcompound of formula (1) in a suitable medium, optionally with one ormore dispersing agents, to produce a fine particle suspension of thecompound. One or more wetting agents may be included in the compositionand a suspending agent may be included to reduce the rate at which theparticles settle. Alternatively, a compound of formula (1) may be drymilled and added to water, containing agents hereinbefore described, toproduce the desired end product.

Aerosol formulations comprise a compound of formula (1) and a suitablepropellant (for example n-butane). A compound of formula (1) may also bedissolved or dispersed in a suitable medium (for example water or awater miscible liquid, such as n-propanol) to provide compositions foruse in non-pressurised, hand-actuated spray pumps.

A compound of formula (1) may be mixed in the dry state with apyrotechnic mixture to form a composition suitable for generating, in anenclosed space, a smoke containing the compound.

Capsule suspensions (CS) may be prepared in a manner similar to thepreparation of EW formulations but with an additional polymerisationstage such that an aqueous dispersion of oil droplets is obtained, inwhich each oil droplet is encapsulated by a polymeric shell and containsa compound of formula (1) and, optionally, a carrier or diluenttherefor. The polymeric shell may be produced by either an interfacialpolycondensation reaction or by a coacervation procedure. Thecompositions may provide for controlled release of the compound offormula (1) and they may be used for seed treatment. A compound offormula (1) may also be formulated in a biodegradable polymeric matrixto provide a slow, controlled release of the compound.

A composition may include one or more additives to improve thebiological performance of the composition (for example by improvingwetting, retention or distribution on surfaces; resistance to rain ontreated surfaces; or uptake or mobility of a compound of formula (1)).Such additives include surface active agents, spray additives based onoils, for example certain mineral oils or natural plant oils (such assoy bean and rape seed oil), and blends of these with otherbio-enhancing adjuvants (ingredients which may aid or modify the actionof a compound of formula (1)).

A compound of formula (1) may also be formulated for use as a seedtreatment, for example as a powder composition, including a powder fordry seed treatment (DS), a water soluble powder (SS) or a waterdispersible powder for slurry treatment (WS), or as a liquidcomposition, including a flowable concentrate (FS), a solution (LS) or acapsule suspension (CS). The preparations of DS, SS, WS, FS and LScompositions are very similar to those of, respectively, DP, SP, WP, SCand DC compositions described above. Compositions for treating seed mayinclude an agent for assisting the adhesion of the composition to theseed (for example a mineral oil or a film-forming barrier).

Wetting agents, dispersing agents and emulsifying agents may be SFAs ofthe cationic, anionic, amphoteric or non-ionic type.

Suitable SFAs of the cationic type include quaternary ammonium compounds(for example cetyltrimethyl ammonium bromide), imidazolines and aminesalts.

Suitable anionic SFAs include alkali metals salts of fatty acids, saltsof aliphatic monoesters of sulphuric acid (for example sodium laurylsulphate), salts of sulphonated aromatic compounds (for example sodiumdodecylbenzenesulphonate, calcium dodecylbenzenesulphonate,butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- andtri-isopropyl-naphthalene sulphonates), ether sulphates, alcohol ethersulphates (for example sodium laureth-3-sulphate), ether carboxylates(for example sodium laureth-3-carboxylate), phosphate esters (productsfrom the reaction between one or more fatty alcohols and phosphoric acid(predominately mono-esters) or phosphorus pentoxide (predominatelydi-esters), for example the reaction between lauryl alcohol andtetraphosphoric acid; additionally these products may be ethoxylated),sulphosuccinamates, paraffin or olefine sulphonates, taurates andlignosulphonates.

Suitable SFAs of the amphoteric type include betaines, propionates andglycinates.

Suitable SFAs of the non-ionic type include condensation products ofalkylene oxides, such as ethylene oxide, propylene oxide, butylene oxideor mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetylalcohol) or with alkylphenols (such as octylphenol, nonylphenol oroctylcresol); partial esters derived from long chain fatty acids orhexitol anhydrides; condensation products of said partial esters withethylene oxide; block polymers (comprising ethylene oxide and propyleneoxide); alkanolamides; simple esters (for example fatty acidpolyethylene glycol esters); amine oxides (for example lauryl dimethylamine oxide); and lecithins.

Suitable suspending agents include hydrophilic colloids (such aspolysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose)and swelling clays (such as bentonite or attapulgite).

A compound of formula (1) may be applied by any of the known means ofapplying fungicidal compounds. For example, it may be applied,formulated or unformulated, to any part of the plant, including thefoliage, stems, branches or roots, to the seed before it is planted orto other media in which plants are growing or are to be planted (such assoil surrounding the roots, the soil generally, paddy water orhydroponic culture systems), directly or it may be sprayed on, dustedon, applied by dipping; applied as a cream or paste formulation, appliedas a vapour or applied through distribution or incorporation of acomposition (such as a granular composition or a composition packed in awater-soluble bag) in soil or an aqueous environment.

A compound of formula (1) may also be injected into plants or sprayedonto vegetation using electrodynamic spraying techniques or other lowvolume methods, or applied by land or aerial irrigation systems.

Compositions for use as aqueous preparations (aqueous solutions ordispersions) are generally supplied in the form of a concentratecontaining a high proportion of the is active ingredient, theconcentrate being added to water before use. These concentrates, whichmay include DCs, SCs, ECs, EWs, MEs SGs, SPs, WPs, WGs and CSs, areoften required to withstand storage for prolonged periods and, aftersuch storage, to be capable of addition to water to form aqueouspreparations which remain homogeneous for a sufficient time to enablethem to be applied by conventional spray equipment. Such aqueouspreparations may contain varying amounts of a compound of formula (1)(for example 0.0001 to 10%, by weight) depending upon the purpose forwhich they are to be used.

A compound of formula (1) may be used in mixtures with fertilisers (forexample nitrogen-, potassium- or phosphorus-containing fertilisers).Suitable formulation types include granules of fertiliser. The mixturessuitably contain up to 25% by weight of the compound of formula (1).

The invention therefore also provides a fertiliser compositioncomprising a fertiliser and a compound of formula (1).

The compositions of this invention may contain other compounds havingbiological activity, for example micronutrients or compounds havingsimilar or complementary fungicidal activity or which possess plantgrowth regulating, herbicidal, insecticidal, nematicidal or acaricidalactivity.

By including another fungicide, the resulting composition may have abroader spectrum of activity or a greater level of intrinsic activitythan the compound of formula (1) alone. Further the other fungicide mayhave a synergistic effect on the fungicidal activity of the compound offormula (1).

The compound of formula (1) may be the sole active ingredient of thecomposition or it may be admixed with one or more additional activeingredients such as a pesticide, fungicide, synergist, herbicide orplant growth regulator where appropriate. An additional activeingredient may: provide a composition having a broader spectrum ofactivity or increased persistence at a locus; synergise the activity orcomplement the activity (for example by increasing the speed of effector overcoming repellency) of the compound of formula (1); or help toovercome or prevent the development of resistance to individualcomponents. The particular additional active ingredient will depend uponthe intended utility of the composition.

Examples of fungicidal compounds which may be included in thecomposition of the invention are AC 382042(N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy) propionamide),acibenzolar-S-methyl, alanycarb, aldimorph, anilazine, azaconazole,azafenidin, azoxystrobin, benalaxyl, benomyl, benthiavalicarb,biloxazol, bitertanol, blasticidin S, boscalid (new name for nicobifen),bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazimchlorhydrate, carboxin, carpropamid, carvone, CGA 41396, CGA 41397,chinomethionate, chlorbenzthiazone, chlorothalonil, chlorozolinate,clozylacon, copper containing compounds such as copper oxychloride,copper oxyquinolate, copper sulphate, copper tallate, and Bordeauxmixture, cyamidazosulfamid, cyazofamid (IKF-916), cyflufenamid,cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulphide1,1′-dioxide, dichlofluanid, diclocymet, diclomezine, dicloran,diethofencarb, difenoconazole, difenzoquat, diflumetorim,O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole,dimethirimol, dimethomorph, dimoxystrobin, diniconazole, dinocap,dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine,doguadine, edifenphos, epoxiconazole, ethaboxam, ethirimol, ethyl(Z)-N-benzyl-N([methyl(methyl-thioethylideneaminooxycarbonyl)amino]thio)-β-alaninate,etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram,fenhexamid, fenoxanil (AC 382042), fenpiclonil, fenpropidin,fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone,fluazinam, fludioxonil, flumetover, flumorph, fluoroimide;fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil,flutriafol, folpet, fosetyl-aluminium, fuberidazole, furalaxyl,furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole,imazalil, imibenconazole, iminoctadine, iminoctadine triacetate,ipconazole, iprobenfos, iprodione, iprovalicarb, isopropanyl butylcarbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LY186054,LY211795, LY 248908, mancozeb, maneb, mefenoxam, mepanipyrim, mepronil,metalaxyl, metalaxyl M, metconazole, metiram, metiram-zinc,metominostrobin, metrafenone, MON65500(N-allyl-4,5-dimethyl-2-trimethylsilylthiophene-3-carboxamide),myclobutanil, NTN0301, neoasozin, nickel dimethyldithiocarbamate,nitrothale-isopropyl, nuarimol, ofurace, organomercury compounds,orysastrobin, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole,oxycarboxin, pefurazoate, penconazole, pencycuron, phenazin oxide,phosphorus acids, phthalide, picoxystrobin, polyoxin D, polyram,probenazole, prochloraz, procymidone, propamocarb, propamocarbhydrochloride, propiconazole, propineb, propionic acid, proquinazid,prothioconazole, pyraclostrobin, pyrazophos, pyrifenox, pyrimethanil,pyroquilon, pyroxyfur, pyrronitrin, quaternary ammonium compounds,quinomethionate, quinoxyfen, quintozene, silthiofam (MON 65500),S-imazalil, simeconazole, sipconazole, sodium pentachlorophenate,spiroxamine, streptomycin, sulphur, tebuconazole, tecloftalam,tecnazene, tetraconazole, thiabendazole, thifluzamide,2-(thiocyanomethylthio)benzothiazole, thiophanate-methyl, thiram,tiadinil, timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon,triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph,trifloxystrobin, triflumizole, triforine, triticonazole, validamycin A,vapam, vinclozolin, XRD-563, zineb, ziram, zoxamide and compounds of theformulae:

The compounds of formula (1) may be mixed with soil, peat or otherrooting media for the protection of plants against seed-borne,soil-borne or foliar fungal diseases.

Some mixtures may comprise active ingredients which have significantlydifferent physical, chemical or biological properties such that they donot easily lend themselves to the same conventional formulation type. Inthese circumstances other formulation types may be prepared. Forexample, where one active ingredient is a water insoluble solid and theother a water insoluble liquid, it may nevertheless be possible todisperse each active ingredient in the same continuous aqueous phase bydispersing the solid active ingredient as a suspension (using apreparation analogous to that of an SC) but dispersing the liquid activeingredient as an emulsion (using a preparation analogous to that of anEW). The resultant composition is a suspoemulsion (SE) formulation.

The invention is illustrated by the following Examples in which thefollowing abbreviations are used:

ml = millilitres g = grammes ppm = parts per million M⁺ = mass ion s =singlet d = doublet br s = broad singlet t = triplet DMSO =dimethylsulphoxide NMR = nuclear magnetic resonance HPLC = highperformance liquid chromatography q = quartet m = multiplet ppm = partsper million m.p. = melting point

EXAMPLE 1

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (Compound No.2 of Table 1)

Stage 1: Preparation of 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide

Step 1: Preparation of 4-amino-4-methylpent-2-yne hydrochloride

3-Amino-3-methylbutyne (commercially available as 90% aqueous solution;16.6 g) was dissolved in dichloromethane (150 ml), dried over sodiumsulphate and filtered to give a solution containing 14.9 g of amine. Tothe stirred solution of amine under an atmosphere of nitrogen at ambienttemperature was added dry triethylamine (48.4 ml).1,2-Bis-(chlorodimethylsilyl)ethane (38.98 g) in dichloromethane (100ml) was then added dropwise, maintaining the reaction temperature at 15°C. by cooling. The mixture was stirred for 3 hours, the colourlesssolid, which had formed during the reaction, was filtered from solutionand the filtrate was evaporated under reduced pressure to give a paste.The paste was extracted into hexane and refiltered. The filtrate wasevaporated under reduced pressure and the oil obtained was distilled togive1-(1,1-dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane,21.5 g, b.p. 41° C. at 0.06 mm Hg pressure.

¹H NMR (CDCl₃) δ: 0.16(12H, s); 0.60(4H,s); 1.48(6H, s); 2.24(1H, s).

Step 2

The product from Step 1 (13.0 g) in dry tetrahydrofuran (140 ml) wascooled to −70° C. under an atmosphere of nitrogen with stirring and asolution of n-butyl lithium (23.1 ml of 2.5M solution in hexanes) wasadded at −65 to −70° C. during 5 minutes. The mixture was allowed towarm to −5° C. and methyl iodide (3.93 ml) was added dropwise over 10minutes. The reaction mixture was allowed to warm to 10° C. when anexothermic reaction occurred. The mixture was maintained at 20° C. bycooling for 2 hours then evaporated under reduced pressure to a smallvolume. The residue was dissolved in hexane, filtered to remove theinsoluble material and evaporated under reduced pressure to give1-(1,1-dimethyl-2-butynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentaneas a yellow oil, 13.0 g.

¹H NMR (CDCl₃) δ: 0.10(12H,s); 0.56(4H, s); 1.40(6H, s); 1.72(3H, s).

Step 3

The product from Step 2 (13.0 g) was added slowly to aqueoushydrochloric acid (35 ml, 4M) at 0° C. with stirring. The emulsionformed was stirred for 0.5 hours then taken to pH14 with aqueous sodiumhydroxide (4M) while maintaining the reaction mixture at 0° C. bycooling in ice. The aqueous mixture was extracted into dichloromethane(three times) and the extracts combined, dried over sodium sulphate andfiltered. The filtrate was made acidic by adding an excess of asaturated solution of hydrogen chloride in 1,4-dioxan. The mixture wasconcentrated under reduced pressure until a colourless precipitate wasformed. Hexane was added to the suspension and the solid was filteredfrom solution. The solid was washed with dry diethyl ether and placedunder vacuum to remove any residual solvents to give the requiredproduct as a colourless solid, 5.0 g.

¹H NMR (d₆-DMSO) δ: 1.74(6H, s); 1.82(3H, s); 8.74(3H, br s).

Step 4: The preparation of 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide

The product from Step 3 (5.0 g) was dissolved in dry dichloromethane(200 ml), cooled to 3° C. with stirring then 2-bromobutyryl bromide(6.25 g) was added followed by dropwise addition of dry triethylamine(10.93 ml), maintaining the reaction at 5° C. The suspension, which hadformed during the reaction, was stirred at ambient temperature for 1hour then water was added. The organic phase was separated, washed withwater, dried over magnesium sulphate then evaporated under reducedpressure. The residue was fractionated by chromatography (silica;hexane/diethyl ether, 3:1 by volume) to give the required product, 5.2g, as a colourless solid, m.p. 79–81° C.

¹H NMR (CDCl₃) δ: 1.04(3H, t); 1.64(6H, s); 1.84(3H, s); 2.04–2.18(2H,m); 4.20–4.24(1H, m); 6.46(1H, br s).

Stage 2

6-Hydroxyquinoline (0.46 g) in dry N,N-dimethylformamide (10 ml) wasadded dropwise to a stirred suspension of sodium hydride (0.10 g, 80%dispersion in mineral oil) in dry N,N-dimethylformamide under anatmosphere of nitrogen at ambient temperature. The green solution wasstirred at ambient temperature for 1 hour and a solution of2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.74 g) in dryN,N-dimethylformamide (10 ml) was added. The mixture was stirred atambient temperature for 18 hours, poured into water and extracted intodiethyl ether (three times). The organic extracts were combined, washedwith dilute aqueous sodium hydroxide, water (twice), dried overmagnesium sulphate and evaporated under reduced pressure to give a gum.The gum was fractionated by chromatography (silica; diethyl ether) togive the required product, 0.44 g, as a colourless gum.

¹H NMR (CDCl₃) δ: 1.06–1.10(3H, t); 1.56–1.60(6H, d); 1.76(3H, s);1.98–2.10(2H, m); 4.54–4.58(1H, m); 6.42(1H, s); 7.10(1H, m);7.36–7.44(2H, m); 8.02–8.06(2H, m); 8.82(1H, d).

EXAMPLE 2

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(1-tert-butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide(Compound No. 50 of Table 1)

Stage 1: Preparation of 4-amino-1-hydroxy-4-methylpent-2-ynehydrochloride

Step 1

1-(1,1-Dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane(22.6 g) in dry tetrahydrofuran (250 ml) was cooled to −50° C. under anatmosphere of nitrogen with stirring and a solution of n-butyl lithium(44 ml, 2.5M solution in hexanes) was added dropwise over 10 minutes.The mixture was stirred for 0.5 hour, allowed to warm to −20° C. thenformaldehyde gas was bubbled through the mixture until no startingmaterial remained, as determined by glc analysis. On complete reactionthe mixture was treated with water, the ether phase separated and theaqueous phase was extracted with ethyl acetate (twice). The organicextracts were combined, washed with water (three times), dried overmagnesium sulphate and evaporated under reduced pressure to give therequired product (24.96 g) as a pale yellow liquid.

¹H NMR (CDCl₃) δ: 0.00(12H, s); 0.46(4H, s); 1.32(6H, s); 4.10(2H, s).

Step 2

The product from Step 1 (24.96 g) was treated with dilute aqueoushydrochloric acid (300 ml) and stirred at ambient temperature for 0.5hour. The mixture was washed with diethyl ether (twice), the aqueousphase was evaporated under reduced pressure, distilled with toluene(twice) to remove residual water and the residual solid obtained wastriturated with hexane to give 4-amino-1-hydroxy-4-methylpent-2-ynehydrochloride (13.1 g) as a cream coloured solid.

¹H NMR (CDCl₃) δ: 1.48(6H, s); 4.06(2H, s); 5.32(1H, s); 8.64(3H, s).

Stage 2: Preparation of 4-amino-1-tert.-butyldimethylsilyloxy-4-methylent-2-yne

4-Amino-1-hydroxy-4-methylpent-2-yne hydrochloride (4.40 g) wasdissolved in dry N,N-dimethylformamide (100 ml) and triethylamine (4.44ml) was added. The suspension was stirred at ambient temperature for 10minutes, imidazole (4.93 g) was added followed by t-butyldimethylsilylchloride (5.24 g) in dry N,N-dimethylformamide (40 ml). The mixture wasstirred at ambient temperature for 18 hours then diluted with water. Themixture was extracted with diethyl ether (three times) and the organicextracts were combined, washed with water (twice) then dried overmagnesium sulphate and evaporated under reduced pressure to give therequired product (6.88 g) as a yellow liquid.

¹H NMR (CDCl₃) δ: 0.04(6H, s); 0.84(9H, s); 1.30(6H, s); 4.22(2H, s).

Stage 3: Preparation of 2-(6-quinolinyloxy butyric acid

Step 1: Preparation of methyl 2-(6-quinolinyloxy)butyrate

6-Hydroxyquinoline (25.1 g), methyl 2-bromobutyrate (32.3 g) andanhydrous potassium carbonate (23.0 g) in dry N,N-dimethylformamide (100ml) were stirred at 100° C. for 3 hours then stored at ambienttemperature for 18 hours. The mixture was added to water, extracted withethyl acetate (three times) and the extracts combined, washed with water(four times) then dried over magnesium sulphate. The solvent wasevaporated under reduced pressure to give the required product (39.0 g)as a red oil.

¹H NMR (CDCl₃) δ: 1.10–1.14(3H, t); 2.04–2.12(2H, q); 3.78(3H, s);4.72–4.76(1H, t); 7.00(1H, d); 7.36–7.40(1H, m); 7.42–7.46(1H, m);8.02–8.04(2H, d); 8.80(1H, d).

Step 2: Preparation of 2-(6-quinolinyloxy)butyric acid

The product from Step 1 (38.8 g) was stirred in a solution of sodiumhydroxide (12.6 g) in water (100 ml) and heated to 90° C. for 3 hoursthen cooled to ambient temperature. The solution was diluted with waterand the aqueous phase was washed with ethyl acetate (twice), acidifiedto pH6 with aqueous hydrochloric acid then extracted with ethyl acetate(three times). The extracts were combined, dried over magnesium sulphateand the solvent evaporated under reduced pressure and the residue waswashed with hexane to give the required product, 8.1 g, as a yellowbrown solid. The aqueous phase was re-extracted with ethyl acetate andprocessed as before to provide further required product (3.7 g).

Stage 4

2-(6-Quinolinyloxy)butyric acid (0.61 g),4-amino-1-tert-butyldimethylsilyloxy-4-methylpent-2-yne (0.57 g) and4-dimethylaminopyridine (0.010 g) in dry dichloromethane (10 ml) werestirred and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.53 g) was added. The mixture was stirred at ambient temperature for3.5 hours, stored for 2 days, diluted with dichloromethane, washed withsaturated aqueous sodium hydrogen carbonate (twice) and then with water.The organic phase was dried over magnesium sulphate and evaporated underreduced pressure to give a yellow oil. The oil was fractionated bychromatography (silica; hexane/ethyl acetate, 3:1 by volume) to give agum that was triturated with hexane to give the required product (0.12g) as a colourless solid, m.p. 78–80° C.

¹H NMR (CDCl₃) δ: 0.08(6H, s); 0.88(9H, s); 1.06–1.10(3H, t);1.62–1.66(6H, d); 2.00–2.10(2H, m); 4.28(2H, s); 4.54–4.58(1H, t);6.44(1H, s); 7.10(1H, s); 7.36–7.44(2H, m); 8.02–8.06(2H, d); 8.80(1H,m).

The hexane washings were evaporated under reduced pressure to give anoil (0.53 g) containing further required product.

EXAMPLE 3

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(1-hydroxy-4-methylpent-2-yn-4-yl) butyramide(Compound No. 10 of Table1)

2-(6-Quinolinyloxy)-N-(1-tert.butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide(0.58 g) in tetrahydrofuran (10 ml) was stirred at 3–5° C. and asolution of tetra n-butylammonium fluoride (2.64 ml of 1M solution intetrahydrofuran) was added dropwise over 5 minutes. On completion ofaddition, the mixture was stirred for 0.5 hour at 0° C., 0.75 hour atambient temperature then stored for 18 hours. The solvent was evaporatedunder reduced pressure and the residue partitioned between ethyl acetateand aqueous ammonium chloride. The organic phase was separated, washedwith aqueous ammonium chloride, brine, dried over magnesium sulphate andevaporated under reduced pressure to give a gum that was fractionated bychromatography (silica; hexane/ethyl acetate, 1:2 by volume) to give therequired product as a colourless glass (0.30 g).

¹H NMR (CDCl₃) δ: 1.06–1.10(3H, t); 1.58(3H, s); 1.60(3H, s);1.98–2.08(3H, m); 4.22–4.24(2H, d); 4.56–4.60(1H, t); 6.42(1H, s);7.10(1H, s); 7.36–7.44(2H, m); 8.04–8.08(2H, d); 8.80(1H, m).

EXAMPLE 4

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl)butyramide(Compound No. 12 of Table 1)

Step 1: Preparation of 4-amino-1-methoxy-4 methylpent-2-ynehydrochloride

To a stirred suspension of sodium hydride (0.45 g, 80% dispersion inmineral oil) in dry N,N-dimethylformamide (2 ml) under an atmosphere ofnitrogen at ambient temperature was added dropwise over 5 minutes asolution of 4-amino-1-hydroxy-4-methylpent-2-yne hydrochloride (0.75 g)in dry N,N-dimethylformamide (20 ml). The mixture was stirred for 2.75hours at ambient temperature then a solution of methyl iodide (0.78 g)in N,N-dimethylformamide (5 ml) was added. The reaction was stirred for2.5 hours, stored for 18 hours then poured into water, extracted withdiethyl ether (three times) and the organic extracts were combined. Thecombined organic phase was extracted with dilute hydrochloric acid(three times) and the aqueous acidic extracts were combined andevaporated under reduced pressure. The residual solid was dried byevaporating under reduced pressure with toluene (twice) to give a yellowgum (0.8 g) containing the required product. The compound wascharacterised from its NMR spectrum.

¹H NMR (CDCl₃) δ:1.78(6H, s); 3.40(3H, s); 4.12(2H, s); 8.90(3H, br s).

Step 2

Triethylamine (0.54 ml) was added to a stirred solution of the productfrom Step 1 (0.8 g) in dry N,N-dimethylformamide (10 ml). The solutionwas stirred for 5 minutes then 1-hydroxybenzotriazole (0.39 g) andN-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (0.55 g)in dry N,N-dimethylformamide (5 ml) were added. The mixture was stirredat ambient temperature for 2 hours, poured into water and the aqueousphase extracted with ethyl acetate (three times). The organic extractswere combined, washed with water (three times), dried over magnesiumsulphate and evaporated under reduced pressure to give a red oil. Theoil was fractionated by chromatography (silica; ethyl acetate) to givethe required product (0.15 g) as a pale yellow gum.

¹H NMR (CDCl₃) δ: 1.06–1.12(3H, t); 1.62(6H, s); 2.00–2.08(2H, m);3.32(3H, s); 4.08–4.24(2H, s); 4.58–4.62(1H, t); 6.44(1H, s); 7.10(1H,m); 7.36–7.46(2H, m); 8.04–8.08(2H, d); 8.82(1H, m).

EXAMPLE 5

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-2-(ethoxy)-N-(2-methylpent-3-yn-2-yl) acetamide(Compound No. 2 of Table 17)

Step 1: Preparation of ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate

Potassium t-butoxide (3.15 g) was dissolved in t-butyl alcohol (20 ml)and stirred for 10 minutes at ambient temperature. 6-Hydroxyquinoline(3.0 g) was added, the resulting dark green solution was stirred for 15minutes, and then ethyl 2-chloro-2-ethoxyacetate (4.22 g, 90% pure)added, followed by a catalytic amount of potassium iodide (0.005 g). Themixture was stirred for 18 hours, poured into water and extracted withchloroform. The organic fraction was washed with brine, water, and driedover magnesium sulphate. The solvent was evaporated to give a brown oil,which was purified by flash chromatography on silica gel, eluting with agradient of ethyl acetate:hexane (1:2 to 4:1) to give ethyl2-(6-quinolinyloxy)-2-(ethoxy)acetate as a pale brown oil (3.68 g).

¹H NMR (CDCl₃) δ ppm: 1.28 (3H, t); 1.31 (3H, t); 3.79 (1H, m); 3.90(1H, m); 4.31 (2H, q); 5.68 (1H, s); 7.38 (2H, dd); 7.51 (1H, dd); 8.06(2H, dd); 8.32 (1H, dd).

Step 2: Preparation of 2-(6-quinolinyloxy)-2-(ethoxy)acetic acid

Ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate (3.68 g) was added to asolution of sodium hydroxide (0.589 g) in water (10 ml) and methanol (30ml) and stirred for 5 minutes. The solution was evaporated under reducedpressure, water added and the aqueous phase was washed with ethylacetate. The aqueous phase was acidified with hydrochloric acid andextracted with ethyl acetate. The extracts were combined, dried overmagnesium sulphate and evaporated under reduced pressure to give2-(6-quinolinyloxy)-2-(ethoxy)acetic acid (1.47 g) as a cream solid.

¹H NMR (CDCl₃) δ ppm: 1.33 (3H, t); 3.98 (1H, m); 5.71 (1H, s); 7.44(1H, dd); 7.52 (2H, m); 8.05 (1H, d); 8.20 (1H, d); 8.84 (1H, dd).

Step 3

Triethylamine (0.3 ml) was added to a stirred solution of4-amino-4-methylpent-2-yne hydrochloride (0.054 g) inN,N-dimethylformamide (2 ml) giving a white suspension.2-(6-Quinolinoxy)-2-(ethoxy)acetic acid (0.1 g) was added followed byN-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (0.077 g)and a catalytic amount of 1-hydroxybenzotriazole (0.005 g), and thewhite suspension was stirred at ambient temperature for 18 hours. Waterwas added and the aqueous phase was extracted with ethyl acetate. Theorganic phase was washed with water, saturated aqueous sodiumbicarbonate and brine, dried over magnesium sulphate and evaporatedunder reduced pressure to give a yellow oil (0.117 g). The oil waspurified by flash chromatography (silica gel; ethyl acetate/hexane, 1:1by volume) to give the required product (0.096 g) as a colourless oil.

¹H NMR (CDCl₃) δ ppm: 1.28 (3H, t); 1.64 (3H, s); 1.66 (3H, s); 1.80(3H, s); 3.70 (1H, m); 3.88 (1H, m); 5.48 (1H, s); 6.79 (1H, bs); 7.37(1H, dd); 7.49 (1H, d); 7.52 (1H, dd); 8.05 (1H, d); 8.08 (1H, d); 8.82(1H, dd).

EXAMPLE 6

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(2-methylpent-3-yn-2-yl)-3-methoxypropionamide(Compound No. 2 of Table 11)

Stage 1: Preparation of 2-bromo-N-(4-methyl ent-2-yn-4-yl)3-methoxypropionamide

Step 1: Preparation of methyl 2-bromo-3-methoxypropionate

Methyl 2,3-dibromopropionate (21.9 g) and trimethylamine N-oxide (0.1 g)in methanol (8 ml) were cooled to −5° C. with stirring under anatmosphere of nitrogen. A methanolic solution of sodium methoxide,freshly prepared from sodium (2.25 g) and methanol (24 ml), was addeddropwise over 15 minutes to the mixture, which was maintained below 0°C. by cooling. On complete addition, the mixture was stirred for afurther 30 minutes then acetic acid (1 ml) was added followed by diethylether (100 ml). The mixture was filtered to remove insoluble salts andthe filtrate evaporated under reduced pressure to give an oil, which wasre-dissolved in a small volume of diethyl ether and re-filtered. Thefiltrate was evaporated under reduced pressure to give the requiredproduct (17.4 g) as a pale yellow oil.

¹H NMR (CDCl₃) δ: 3.41(3H, s); 3.74(1H, dd); 3.82(3H, s); 3.92(1H, dd);4.34(1H, dd).

Step 2: Preparation of 2-bromo-3-methoxypropionic acid

Methyl 2-bromo-3-methoxypropionate (1.00 g) in tetrahydrofuran (8 ml)was stirred at 10° C. and lithium hydroxide monohydrate (0.21 g) inwater (1.5 ml) was added dropwise. On complete addition, the mixture wasstirred for 1.5 hours, the colourless solution was evaporated underreduced pressure to a small volume then the aqueous solution was takento pH 3 with dilute sulphuric acid. The mixture was extracted withdiethyl ether (50 ml) and the organic phase separated, washed withbrine, dried over magnesium sulphate then evaporated under reducedpressure to give the required product (0.6 g) as a colourless liquid.

¹H NMR (CDCl₃) δ: 3.45(3H, s); 3.78(1H, m); 3.92(1H, m); 4.38(1H, m);6.65(1H, br s).

Step 3: Preparation of 2-bromo-N-(4-methylpent-2-yn-4-yl)3-methoxypropionamide

2-Bromo-3-methoxypropionic acid (0.366 g) was dissolved in drydichloromethane (4 ml) containing dry N,N-dimethylformamide (0.05 ml)with stirring and oxalyl chloride (0.254 g) was added. The mixture wasstirred at ambient temperature for 2 hours then evaporated under reducedpressure to give 2-bromo-3-methoxypropionic acid chloride (C═O, ν 1780cms⁻¹). The acid chloride was dissolved in dry dichloromethane (6 ml)and 4-amino-4-methylpent-2-yne hydrochloride (0.267 g) was added thenthe mixture was cooled to 3° C. and triethylamine (0.404 g) was addeddropwise, keeping the reaction temperature between 0–5° C. Thesuspension that had formed was stirred at ambient temperature for 1hour, diluted with further dichloromethane, washed with hydrochloricacid (2M) and the organic phase separated, dried over magnesium sulfatethen evaporated under reduced pressure to give a gum. The gum wasfractionated by chromatography (silica: hexane/ethyl acetate, 3:2 byvolume) to give the required product (0.3 g) as a colourless solid.

¹H NMR (CDCl₃) δ: 1.63(6H, s); 1.82(3H, s); 3.44(3H, s); 3.88(2H, m);4.32(1H, m); 6.62(1H, s).

Stage 2

6-Hydroxyquinoline (0.083 g), anhydrous potassium carbonate (0.087 g)and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide (0.150 g)in dry N,N-dimethylformamide (3 ml) were stirred and heated to 80° C.for 5 hours then stored for 72 hours at ambient temperature. The yellowsuspension was diluted with water, extracted with ethyl acetate and theorganic phase was separated then washed with water, dried over magnesiumsulphate and evaporated under reduced pressure to a gum. The gum wasfractionated by chromatography (silica; ethyl acetate:hexane, 3:2 byvolume) to give the required product (0.055 g) as a colourless gum.

¹H NMR (CDCl₃) δ: 1.58(3H, s); 1.60(3H, s); 1.78(3H, s); 3.46(3H, s);3.95(2H, m); 4.78(1H, m); 6.60(1H, s); 7.18(1H, m); 7.40(1H, m);7.50(1H, m); 8.08(2H, m); 8.83(1H, m).

EXAMPLE 7

This Example Illustrates the Preparation of2-(6-quinazolinoxy)-N-(4-methylpent-2-yn-4-yl) butyramide (Compound No.2 of Table 20)

6-Hydroxyquinazoline (0.060 g, prepared as described in J. Chem. Soc.(1952), 4985) and 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.101g) were dissolved in dry N,N-dimethylformamide (2 ml) containinganhydrous potassium carbonate (0.088 g). The mixture was stirred andheated to 80° C. for 5 hours then allowed to cool to ambient temperatureand stored for 18 hours. The brown suspension was diluted with water,extracted into ethyl acetate and the organic phase separated, washedwith water, dried over magnesium sulphate and evaporated under reducedpressure to give a pale brown oil. The oil was fractionated bychromatography (silica; ethyl acetate/hexane, 4:1 by volume) to give thetitle product (0.12 g) as a pale brown gum.

¹H NMR (CDCl₃) δ: 1.04(3H, t); 1.53(6H, s); 1.72(3H, s); 1.95–2.05(2H,m); 4.54(1H, m); 6.30(1H, s); 7.14(1H, m); 7.60(1H, dd); 7.97(1H, d);9.20(1H, s); 9.25(1H, s).

EXAMPLE 8

In a similar procedure to Example 1,7-hydroxyisoquinoline (commerciallyavailable) and 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide werereacted to give 2-(7-isoquinolinyloxy)-N-(4-methylpent-2-yn-4-yl)butyramide (Compound No. 2 of Table 39) as a colourless solid, m.p.149–150° C.

¹H NMR (CDCl₃) δ: 1.08(3H, t); 1.58(3H, s); 1.59(3H, s); 1.77(3H, s);1.98–2.12(2H, m); 4.58(1H, m); 6.40(1H, s); 7.26(1H, d); 7.42(1H, dd);7.61(1H, d); 7.79(1H, d); 8.45(1H, d); 9.14(1H, s).

EXAMPLE 9

In a similar procedure to Example 6,7-hydroxyisoquinoline (commerciallyavailable) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamidewere reacted to give2-(7-isoquinolinyloxy)-N-(2-methylpent-3-yn-2-yl)-3-methoxypropionamide(Compound No. 2 of Table 49) as a colourless solid, m.p. 155-156° C.

¹H NMR (CDCl₃) δ: 1.59(3H, s); 1.60(3H, s); 1.77(3H, s); 3.45(3H, s);3.88–3.96(2H, m); 4.78(1H, m); 6.54(1H, s); 7.31(1H, d); 7.47(1H, dd);7.61(1H, d); 7.80(1H, d); 8.46(1H, d); 9.14(1H, s).

EXAMPLE 10

This Example Illustrates the Preparation of2-(3-bromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide(Compound No. 2 of Table 77) and2-(3,8-dibromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide(Compound No. 2 of Table 115)

Stage 1: Preparation of 3-bromo-6-hydroxyquinoline and3,8-dibromo-6-hydroxyquinoline

Step 1: Preparation of 3-bromo-6-nitroquinoline and3,8-dibromo-6-nitroquinoline

In a modification of the procedure described in Liebigs Ann Chem,(1966), 98–106 to make 3-bromo-6-nitroquinoline, 6-nitroquinoline (5.5g) in carbon tetrachloride (200 ml) containing pyridine (5.0 g) wastreated with bromine (15.3 g) and heated to reflux until all the6-nitroquinoline had reacted. The reaction mixture was cooled to ambienttemperature, stored for 18 hours then partitioned between chloroform andhydrochloric acid (2M). The mixture was filtered and the organic phasewas separated, washed with saturated aqueous sodium hydrogen carbonate,dried over magnesium sulphate then evaporated under reduced pressure togive a pale yellow solid. The solid was recrystallised from glacialacetic acid to give a mixture containing 3-bromo-6-nitroquinoline (4parts) and 3,8-dibromo-6-nitroquinoline (1 part) as a pale yellow solid(4.06 g).

Step 2: Preparation of 6-amino-3-bromoquinoline and6-amino-3,8-dibromoquinoline

The product from Step 1 (4.0 g) was suspended in a mixture ofpropan-2-ol (15 ml), water (8 ml) and concentrated hydrochloric acid(0.5 ml) at ambient temperature with stirring. To the mixture was addediron powder (6.0 g) in portions resulting in an exothermic reactionproducing a dark red suspension. The suspension was cooled to ambienttemperature, extracted into aqueous hydrochloric acid (2M), filtered andwashed with diethyl ether. The aqueous acidic phase was separated, madebasic with aqueous sodium hydroxide (2M) and the thick precipitate thatwas produced was extracted with ethyl acetate (twice). The extracts werecombined, washed with brine then dried over magnesium sulphate andevaporated under reduced pressure to give a pale brown solid. The solidwas fractionated by chromatography (silica) eluting first withdichloromethane to provide 6-amino-3,8-dibromoquinoline, 0.15 g (MH⁺301, 2×Br) then with hexane/ethyl acetate (1:1 by volume) to give6-amino-3-bromoquinoline, 1.0 g, m.p. 151–2° C. (MH⁺ 223, 1×Br).

Step 3: Preparation of 3,8-dibromo-6-hydroxyquinoline

6-Amino-3,8-dibromoquinoline (0.15 g) was suspended in phosphoric acid(75%, 11 ml) and heated in a sealed glass, tube at 180° C. for 72 hours.The mixture was allowed to cool to ambient temperature, diluted with ice(50 ml) and taken to pH 2 with aqueous sodium hydroxide (4M). The brownsuspension that formed was extracted with ethyl acetate (twice), driedover magnesium sulphate then evaporated under reduced pressure to give3,8-dibromo-6-hydroxyquinoline (M⁺−H 300, 2×Br) as a dark red solid thatwas used in the next stage without further purification, ¹H NMR (d6DMSO) δ: 7.14(1H, d); 7.60(1H, d); 8.52(1H, d); 8.71(1H, d). In asimilar procedure to Step 3, 6-amino-3-bromoquinoline was converted to3-bromo-6-hydroxyquinoline, brown solid, ¹H NMR (d6 DMSO) δ: 7.19(1H,d); 7.40(1H, dd); 7.92(1H, d); 8.66(1H, s); 8.79(1H, s).

Stage 2: Preparation of2-(3-bromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide

To a stirred mixture of 3-bromo-6-hydroxyquinoline (0.179 g) andanhydrous potassium carbonate (0.121 g) in dry N,N-dimethylformamide (2ml) at 80° C. was added 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide(0.197 g) and the reaction maintained at this temperature for 15 hours.The brown suspension produced was cooled to ambient temperature, pouredinto water and extracted with diethyl ether. The extract was washed withwater, dried over magnesium sulphate then evaporated under reducedpressure to give a brown gum. The gum was fractionated by chromatography(silica; hexane/ethyl acetate) to give2-(3-bromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (0.125g) as a colourless solid, m.p. 109–112° C., ¹H NMR (CDCl₃) δ: 1.08(3H,t); 1.58 (3H, s); 1.59(3H, s); 1.77(3H, s); 1.99–2.06(2H, m); 4.54(1H,t); 6.37(1H, s); 7.02(1H, m); 7.42(1H, dd); 8.02(1H, d); 8.19(1H, m);8.78(1H,m).

In a similar procedure, 3,8-dibromo-6-hydroxyquinoline was reacted with2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give2-(3,8-dibromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide asa colourless gum, ¹H NMR (CDCl₃) δ: 1.07(3H, t); 1.59 (3H, s); 1.60(3H,s); 1.78(3H, s); 1.99–2.06(2H, m); 4.52(1H, t); 6.30(1H, s); 7.00(1H,m); 7.82(1H, dd); 8.21(1H, d); 8.88(1H, m).

EXAMPLE 11

This Example Illustrates the Preparation of2-(3-chloro-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide(Compound No. 2 of Table 58)

Stage 1: Preparation of 3-chloro-6-hydroxyquinoline

3-Bromo-6-hydroxyquinoline (2.75 g) and cuprous chloride (9 g) in dryN-methylpyrrolidin-2-one (25 ml) were stirred and heated at 150° C.under an atmosphere of nitrogen for 2 hours. The dark red suspension wascooled to ambient temperature, poured into water then treated withsufficient aqueous ammonia to dissolve the solid material. The bluesolution was taken to pH 5–6 with hydrochloric acid (2M) then ethylacetate was added. The mixture was filtered and the insoluble solidswashed with ethyl acetate. The organic component of the filtrate wasseparated and the aqueous phase was further extracted with ethylacetate. The ethyl acetate fractions were combined, washed with brine,dried over magnesium sulphate then evaporated under reduced pressure togive a solid. The solid was fractionated by chromatography (silica;hexane/ethyl acetate, 2:1 by volume) to give 3-chloro-6-hydroxyquinolineas a pale yellow solid, 0.95 g. (M⁺ 179, 1×Cl). ¹H NMR (CDCl₃) δ:7.06(1H, d); 7.35(1H, dd); 7.91(1H, d); 7.96(1H, d); 8.59(1H, d);9.55(1H, s).

Stage 2

To a stirred mixture of 3-chloro-6-hydroxyquinoline (0.130 g) andanhydrous potassium carbonate (0.110 g) in dry N,N-dimethylformamide (3ml) at 80° C. was added 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide(0.197 g) and the reaction maintained at this temperature for 6 hours.The brown suspension produced was cooled to ambient temperature, pouredinto water and extracted with diethyl ether. The extract was washed withwater, dried over magnesium sulphate then evaporated under reducedpressure to give a brown gum. The gum was fractionated by chromatography(silica; hexane/ethyl acetate 4:1 by volume) to give2-(3-chloro-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide(0.167 g) as a colourless solid, m.p. 105–107° C., ¹H NMR (CDCl₃) δ:1.08(3H, t); 1.58 (3H, s); 1.59(3H, s); 1.77(3H, s); 1.99–2.08(2H, m);4.55(1H, t); 6.37(1H, s); 7.02(1H, d); 7.41(1H, dd); 8.01(1H, d);8.02(1H, d); 8.70(1H, m); 8.78(1H,m).

EXAMPLE 12

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide (Compound No. 12 of Table 11) and2-(3-bromo-6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide (Compound No. 12 of Table 87)Stage 1: Preparation of 2-bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide

2-Bromo-3-methoxypropionic acid (0.51 g) was dissolved in drydichloromethane (10 ml) containing dry N,N-dimethylformamide (0.05 ml)with stirring and oxalyl chloride (0.36 g) was added. The mixture wasstirred at ambient temperature for 2 hours then evaporated under reducedpressure to give 2-bromo-3-methoxypropionic acid chloride (C═O, ν 1780cms⁻¹). The acid chloride was dissolved in dry dichloromethane (5 ml)and added to 4-amino-1-methoxy-4-methylpent-2-yne hydrochloride (0.46 g)in dry dichloromethane (10 ml) at 0° C. with stirring. Triethylamine(0.78 ml) was added dropwise, while keeping the reaction temperaturebetween 4–9° C. The suspension that had formed was stirred at ambienttemperature for 2 hours, stored at ambient temperature for 18 hours,diluted with further dichloromethane and washed with aqueous sodiumhydrogen carbonate then water (twice). The organic phase was separated,dried over magnesium sulphate and evaporated under reduced pressure togive a gum. The gum was fractionated by chromatography (silica:hexane/ethyl acetate) to give the required product (0.36 g) as acolourless oil, ¹H NMR (CDCl₃) δ: 1.66(6H, s); 3.38(3H, s); 3.44(3H, s);3.82–3.90(2H, q); 4.12(2H, s); 4.30–4.32(1H, t); 6.62(1H, s).

Stage 2

In a similar procedure to Example 6 Stage 2, 6-hydroxyquinoline wasreacted with 2-bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide to give2-(6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide as a colourless oil. ¹H NMR (CDCl₃) δ: 1.60(3H,s); 1.62(3H, s); 3.34(3H, s); 3.44(3H, s); 3.90–3.94(2H, m); 4.06(2H,s); 4.76–4.80(1H, m); 6.60(1H, s); 7.14–7.16(1H, m); 7.36–7.40(1H, m);7.46–7.50(1H, m); 8.04–8.08(2H, d); 8.82–8.84(1H, m).

Stage 3

In a similar procedure to Example 6 Stage 2, 3-bromo-6-hydroxyquinolinewas reacted with 2-bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide to give2-(3-bromo-6-quinolinyloxy)-N-(1-methoxy-4-methylpent-2-yn-4-yl)3-methoxypropionamide as a gum. ¹H NMR (CDCl₃) δ: 1.58(3H, s); 1.59(3H,s); 1.77(3H, s0; 3.44(3H, s); 3.87–3.95(2H, m); 4.73(1H, m); 6.52(1H,s); 7.08(1H, m); 7.48(1H, dd); 8.02(1H, d); 8.21(1H, m); 8.79(1H, m).

EXAMPLE 13

This Example Illustrates the Preparation of2-(6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide 1-oxide(Compound No. 2 of Table 134)

2-(6-Quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (1.0 g) indichloromethane (25 ml) was cooled to 0° C. with stirring and3-chloroperbenzoic acid (1.21 g, 50%) was added in portions then stirredfor a further 15 minutes at 0° C. followed by 1.5 hours at ambienttemperature. The mixture was washed with aqueous sodium hydrogencarbonate (three times), water (twice), dried over magnesium sulphatethen evaporated under reduced pressure to give a gum which wastriturated with diethyl ether to give the required product as a palebrown solid, 0.75 g, m.p. 140–143° C., ¹H NMR (CDCl₃) δ: 1.06–1.10(3H,t); 1.56(3H, s); 1.58(3H, s); 1.76(3H, s); 2.00–2.08(2H, m); 4.56(1H,t); 6.32(1H, s); 7.14 (1H, m); 7.28–7.30(1H, d); 7.44–7.46(1H, d);7.62–7.64(1H,d); 8.42–8.44(1H, d); 8.70–8.72(1H, d).

EXAMPLE 14

This Example Illustrates the Preparation of2-(3-cyano-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide(Compound No. 2 of Table 96)

Stage 1: Preparation of 3-cyano-6-hydroxyquinoline [Reference LiebigsAnn Chem (1966) 98–106]

3-Bromo-6-hydroxyquinoline (1.12 g) in dry N-methylpyrrolidin-2-one (10ml) was treated with cuprous cyanide (0.55 g) and stirred at 150° C. for7 hours under an atmosphere of nitrogen then stored at ambienttemperature for 18 hours. The mixture was treated with sodium cyanide(1.5 g) in water (5 ml) and heated at 75° C. for 15 minutes. 10% Aqueousammonium chloride solution (25 ml) was added and the mixture cooled toambient temperature. The reaction mixture was extracted with ethylacetate and the organic phase separated, washed with water, dried overmagnesium sulphate and evaporated under reduced pressure to give ayellow brown solid. The solid was fractionated by chromatography to givethe required product as a yellow solid.

Stage 2

In a similar procedure to Example 6 Stage 2, 3-cyano-6-hydroxyquinolinewas reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give2-(3-cyano-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide as apale yellow solid, m.p. 116–118° C., ¹H NMR (CDCl₃) δ: 1.08(3H, t);1.61(3H, s); 1.63(3H, s); 1.80(3H, s); 2.07–2.13(2H, m); 4.72(1H, t);6.46(1H, s); 7.50 (1H, m); 7.57(1H, dd); 7.71(1H, d); 8.17(1H,d);8.92(1H, d).

EXAMPLE 15

This Example Illustrates the Preparation of2-(3-bromo-6-quinolinyloxy)-N-(1-cyano-6-methylhept-4-yn-6-yl)butyramide (Compound No. 90 of Table 77) and2-(3-bromo-6-quinolinyloxy)-N-(1-chloro-6-methylhept-4-yn-6-yl)butyramide (Compound No. 91 of Table 77)

Stage 1: The preparation of 2-bromo-N-(1-chloro-6-methylhept-4-yn-6-yl)butyramide

Step 1: Preparation of6-(1-chloro-6-methylhept-4-yn-6-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane

n-Butyl lithium (97.6 ml, 2.5M in hexanes) was added dropwise over 0.5hours to a stirred solution of1-(1,1-dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane(55.1 g) in dry tetrahydrofuran (450 ml) under an atmosphere of nitrogenat −70° C. The mixture was stirred for 1.5 hours at −70° C., allowed towarm to −15° C. then a solution of 1-chloro-3-iodopropane (55.0 g) indry tetrahydrofuran (50 ml) was added dropwise over 20 minutes whilstallowing the reaction temperature to slowly warm to 0° C. On completeaddition, the reaction mixture was stirred at ambient temperature for4.25 hours then stored for 18 hours. The mixture was diluted with waterand extracted with ethyl acetate (twice). The extracts were combined,washed with water (three times), dried over magnesium sulphate thenevaporated under reduced pressure to give the required product as anorange liquid, 78.5 g, ¹H NMR (CDCl₃) δ: 0.00(12H,s); 0.46(4H, s);1.30(6H, s); 1.76(2H, m); 2.18(2H, t); 2.46(2H, t).

Step 2: Preparation of 1-chloro-6-methylhept-4-yn-6-ylaminehydrochloride

The product from Step 1 (78.5 g) was stirred at −5° C. and diluteaqueous hydrochloric acid (785 ml, 2M) was added slowly whilstmaintaining the reaction temperature below 30° C. during the addition.On complete addition, the mixture was stirred for a further 1 hour atambient temperature, washed with diethyl ether (twice), evaporated underreduced pressure and the residual water removed by azeotropicdistillation with toluene. The solid obtained was dissolved indichloromethane, dried over magnesium sulphate and evaporated underreduced pressure to give the required product as a cream coloured solid,36.5 g, ¹H NMR (CDCl₃) δ: 1.74(6H, s); 1.97(2H, m); 2.39(2H, m);3.68(2H, t); 8.80(3H, broad s).

Step 3: The preparation of 2-bromo-N-(1-chloro-6-methylhept-4-yn-6-yl)butyramide

The product from Step 2 (12.2 g) was suspended in dry dichloromethane(300 ml), cooled to 5° C. with stirring and dry triethylamine (18.1 ml)was added. The mixture was stirred for 0.25 hours and 2-bromobutyrylbromide (14.3 g) in dichloromethane (25 ml) was added dropwise over 0.5hours at 10–18° C. The mixture was stirred for a further 0.5 hours thenallowed to warm to ambient temperature for 2 hours and stored for 18hours. Water was added and the organic phase was separated, washed withwater (three times), dried over magnesium sulphate then evaporated underreduced pressure to give the required product as a dark yellow oil, 17.4g, ¹H NMR (CDCl₃) δ: 1.04(3H, t); 1.62(6H, s); 1.96(2H, m); 2.10(2H, m);2.38(2H, m); 3.66(2H, t); 4.12(1H, t); 6.44(1H, s).

Stage 2

In a similar procedure to Example 6 Stage 2, 3-bromo-6-hydroxyquinolinewas reacted with 2-bromo-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramideto give 2-(3-bromo-6-quinolinyloxy)-N-(1-chloro-6-methylhept-4-yn-6-yl)butyramide as a colourless oil. ¹H NMR (CDCl₃) δ: 1.04–1.10(3H, t);1.60(6H, s); 1.86–1.94(2H, m); 2.00–2.06(2H, m); 2.32–2.36(2H, t);3.60–3.64(2H, t); 4.56(1H, t); 6.34(1H, s); 7.02 (1H, m); 7.42–7.46(1H,dd); 8.03 (1H, d); 8.22(1H, s); 8.78(1H, s).

Stage 3

The product from Stage 2 (0.19 g) was dissolved in dryN,N-dimethylformamide (4 ml) containing potassium cyanide (0.056 g) withstirring and heated to 100° C. for 6 hours then cooled to ambienttemperature and stored for 2 days. The mixture was diluted with waterand extracted with ethyl acetate (three times). The extracts werecombined, washed with water (twice), dried over magnesium sulphate andevaporated under reduced pressure to give a yellow gum. The gum wasfractionated by chromatography (silica; hexane/ethyl acetate, 1:1 byvolume) to give2-(3-bromo-6-quinolinyloxy)-N-(1-cyano-6-methylhept-4-yn-6-yl)butyramide as a yellow gum, 0.080 g, ¹H NMR (CDCl₃) δ: 1.04–1.10(3H, t);1.56(6H, s); 1.78–1.84(2H, m); 2.00–2.08(2H, m); 2.32–2.36(2H, t);2.48–2.52(2H, t); 4.58(1H, t); 6.36(1H, s); 7.02 (1H, d); 7.40–7.44(1H,dd); 8.02(1H, d); 8.22(1H, s); 8.80(1H, s).

EXAMPLE 16

This Example Illustrates the Fungicidal Properties of Compounds ofFormula (1)

The compounds were tested in a leaf disk assay, with methods describedbelow. The test compounds were dissolved in DMSO and diluted into waterto 200 ppm. In the case of the test on Pythium ultimum, they weredissolved in DMSO and diluted into water to 20 ppm.

Erysiphe graminis f.sp. hordei (barley powdery mildew): Barley leafsegments were placed on agar in a 24-well plate and sprayed with asolution of the test compound. After allowing to dry completely, forbetween 12 and 24 hours, the leaf disks were inoculated with a sporesuspension of the fungus. After appropriate incubation the activity of acompound was assessed four days after inoculation as preventivefungicidal activity.

Erysiphe graminis f.sp. tritici (wheat powdery mildew): Wheat leafsegments were placed on agar in a 24-well plate and sprayed with asolution of the test compound. After allowing to dry completely, forbetween 12 and 24 hours, the leaf disks were inoculated with a sporesuspension of the fungus. After appropriate incubation the activity of acompound was assessed four days after inoculation as preventivefungicidal activity.

Puccinia recondita f.sp. tritici (wheat brown rust): Wheat leaf segmentswere placed on agar in a 24-well plate and sprayed with a solution ofthe test compound. After allowing to dry completely, for between 12 and24 hours, the leaf disks were inoculated with a spore suspension of thefungus. After appropriate incubation the activity of a compound wasassessed nine days after inoculation as preventive fungicidal activity.

Septoria nodorum (wheat glume blotch): Wheat leaf segments were placedon agar in a 24-well plate and sprayed with a solution of the testcompound. After allowing to dry completely, for between 12 and 24 hours,the leaf disks were inoculated with a spore suspension of the fungus.After appropriate incubation the activity of a compound was assessedfour days after inoculation as preventive fungicidal activity.

Pyrenophora teres (barley net blotch): Barley leaf segments were placedon agar in a 24-well plate and sprayed with a solution of the testcompound. After allowing to dry completely, for between 12 and 24 hours,the leaf disks were inoculated with a spore suspension of the fungus.After appropriate incubation the activity of a compound was assessedfour days after inoculation as preventive fungicidal activity.

Pyricularia oryzae (rice blast): Rice leaf segments were placed on agarin a 24-well plate and sprayed with a solution of the test compound.After allowing to dry completely, for between 12 and 24 hours, the leafdisks were inoculated with a spore suspension of the fungus. Afterappropriate incubation the activity of a compound was assessed four daysafter inoculation as preventive fungicidal activity.

Botrytis cinerea (grey mould): Bean leaf disks were placed on agar in a24-well plate and sprayed with a solution of the test compound. Afterallowing to dry completely, for between 12 and 24 hours, the leaf diskswere inoculated with a spore suspension of the fungus. After appropriateincubation the activity of a compound was assessed four days afterinoculation as preventive fungicidal activity.

Phytophthora infestans (late blight of potato on tomato): Tomato leafdisks were placed on water agar in a 24-well plate and sprayed with asolution of the test compound. After allowing to dry completely, forbetween 12 and 24 hours, the leaf disks were inoculated with a sporesuspension of the fungus. After appropriate incubation the activity of acompound was assessed four days after inoculation as preventivefungicidal activity.

Plasmopara viticola (downy mildew of grapevine): Grapevine leaf diskswere placed on agar in a 24-well plate and sprayed a solution of thetest compound. After allowing to dry completely, for between 12 and 24hours, the leaf disks were inoculated with a spore suspension of thefungus. After appropriate incubation the activity of a compound wasassessed seven days after inoculation as preventive fungicidal activity.

Pythium ultimum (Damping off): Mycelial fragments of the fungus,prepared from a fresh liquid culture, were mixed into potato dextrosebroth. A solution of the test compound in dimethyl sulphoxide wasdiluted with water to 20 ppm then placed into a 96-well microtiter plateand the nutrient broth containing the fungal spores was added. The testplate was incubated at 24° C. and the inhibition of growth wasdetermined photometrically after 48 hours.

The following Compounds [Compound No (Table)] gave more than 60% controlof the following fungal infections at 200 ppm:

Phytophthora infestans: 2(1), 10(1), 12(1), 50(1), 2(20), 2(58), 2(77),90(77), 91(77).

Plasmopara viticola: 2(1), 2(49), 2(58), 2(77), 90(77), 91(77), 2(96),2(115).

Erysiphe graminis f.sp. hordei: 10(1), 2(17).

Erysiphe graminis f.sp tritici: 10(1), 50(1), 2(77), 91(77), 2(115).

Botrytis cinerea: 2(77), 2(115).

Puccinia recondita f.sp. tritici: 90(77).

Septoria nodorum: 10(1).

Pyrenophora teres: 2(20).

The following Compounds gave more than 60% control of the followingfungal infection at 20 ppm:

Pythium ultimum: 2(1), 10(1), 12(1), 50(1), 2(11), 12(11), 2(17), 2(20), 2(39), 2(49), 2(77), 90(77), 91(77), 2(115), 2(134).

1. A compound of the general formula (1):

wherein one of X and Y is N or N-oxide and the other is CR or both of Xand Y are N; Z is H, halo, C₁₋₆ alkyl optionally substituted with haloor C₁₋₄ alkoxy, C₃₋₆ cycloalkyl optionally substituted with halo or C₁₋₄alkoxy, C₂₋₄ alkenyl optionally substituted with halo, C₂₋₄ alkynyloptionally substituted with halo, C₁₋₆ alkoxy optionally substitutedwith halo or C₁₋₄ alkoxy, C₂₋₄ alkenyloxy optionally substituted withhalo, C₂₋₄ alkynyloxy optionally substituted with halo, cyano, nitro,C₁₋₄ alkoxycarbonyl, —OSO₂R′, S(O)_(n)R′, —COR″, —CONR″R″′, —CR″═NOR′,NR″R″′, NR″COR′, NR″CO₂R′ where n is 0, 1 or 2, R′ is C₁₋₆ alkyloptionally substituted with halogen and R″ and R″′ are independently Hor C₁₋₆ alkyl or, in the case of —CONR″R″′, may join to form a 5- or6-membered ring containing a single nitrogen atom, saturated carbonatoms and optionally a single oxygen atom; R is H, halo, C₁₋₈ alkyl,C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈alkylthio, nitro, amino, mono- or di-(C₁₋₆)alkylamino, mono- ordi-(C₂₋₆)alkenylamino, mono- or di-(C₂₋₆)alkynylamino, formylamino, C₁₋₄alkyl(formyl)amino, C₁₋₄ alkylcarbonylamino, C₁₋₄ alkoxycarbonylamino,C₁₋₄ alkyl(C₁₋₄ alkylcarbonyl)amino, cyano, formyl, C₁₋₄ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, aminocarbonyl, mono- ordi-(C₁₋₄)alkylaminocarbonyl, carboxy, C₁₋₄ alkylcarbonyloxy,aryl(C₁₋₄)alkylcarbonyloxy, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl orC₁₋₄ alkylsulphonyloxy; R₁ is C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynylin which the alkyl, alkenyl and alkynyl groups are optionallysubstituted on their terminal carbon atom with one, two or three halogenatoms, with a cyano group, with a C₁₋₄ alkylcarbonyl group, with a C₁₋₄alkoxycarbonyl group or with a hydroxy group, or R₁ is alkoxyalkyl,alkylthioalkyl, alkylsulphinylalkyl or alkylsulphonylalkyl in which thetotal number of carbon atoms is 2 or 3, or R₁ is a straight-chain C₁₋₄alkoxy group; R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkoxymethyl or benzyloxymethylin which the phenyl ring of the benzyl moiety is optionally substitutedwith C₁₋₄ alkoxy; R₃ and R₄ are independently H, C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl provided that both are not H and that when bothare other than H their combined total of carbon atoms does not exceed 4,or R₃ and R₄ join with the carbon atom to which they are attached toform a 3 or 4 membered carbocyclic ring optionally containing one O, Sor N atom and optionally substituted with halo or C₁₋₄ alkyl; and R₅ isH, C₁₋₄ alkyl or C₃₋₆ cycloalkyl in which the alkyl or cycloalkyl groupis optionally substituted with halo, hydroxy, C₁₋₆ alkoxy, cyano, C₁₋₄alkylcarbonyloxy, aminocarbonyloxy, mono- ordi(C₁₋₄)alkylaminocarbonyloxy, —S(O)_(n)(C₁₋₆)alkyl where n is 0, 1 or2, triazolyl (e.g. 1,2,4-triazol-1-yl), tri(C₁₋₄)alkylsilyloxy,optionally substituted phenoxy, optionally substituted thienyloxy,optionally substituted benzyloxy or optionally substitutedthienylmethoxy, or R₅ is optionally substituted phenyl, optionallysubstituted thienyl or optionally substituted benzyl, in which theoptionally substituted phenyl and thienyl rings of the R₅ values areoptionally substituted with one, two or three substituents selected fromhalo, hydroxy, mercapto, C₁₋₄ alkyl, C₂₋₄, alkenyl, C₂₋₄ alkynyl, C₁₋₄alkoxy, C₂₋₄ alkenyloxy, C₂₋₄ alkynyloxy, halo (C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, halo(C₁₋₄)alkylthio,hydroxy(C₁₋₄)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano,thiocyanato, isothiocyanato, nitro, —NR^(m)R^(n), —NHCOR^(m),—NHCONR^(m)R^(n), —CONR^(m)R^(n), —SO₂R^(m), —OSO₂R^(m), —COR^(m),—CR^(m)═NR^(n) or —N═CR^(m)R^(n), in which R^(m) and R^(n) areindependently hydrogen, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, C₁₋₄ alkoxy,halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl, the phenyl and benzyl groupsbeing optionally substituted with halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy. 2.A compound according to claim 1 wherein R₅ is other than H.
 3. Acompound according to claim 1 wherein R is H or halo, cyano.
 4. Acompound according to claim 1, wherein R₁ is methyl, ethyl, n-propyl,2,2,2-trifluoromethyl, cyanomethyl, acetylmethyl, methoxycarbonylmethyl,methoxycarbonylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl,methylthiomethyl, ethoxymethyl, 2-methoxyethyl, 2-methylthioethyl,methoxy, ethoxy, n-propoxy or n-butoxy.
 5. A compound according to claim1, wherein R₁ is ethyl, methoxy, ethoxy or methoxymethyl.
 6. A compoundaccording to claim 1, wherein R₂ is H.
 7. A compound according to claim1, wherein both R₃ and R₄ are methyl.
 8. A compound according to claim1, wherein R₅ is H, methyl, hydroxymethyl, methoxymethyl,1-methoxyethyl, tert-butyldimethylsiloxymethyl, 3-cyanopropyl,3-methoxypropyl, 3-(1,2,4-triazol-1-yl)propyl, 3-methylthiopropyl,3-methanesulphinylpropyl or 3-methanesulphonylpropyl.
 9. A compoundaccording to claim 1 wherein one of X and Y is N and the other is CR orboth of X and Y are N; Z is H; R is H, halo, C₁₋₈ alkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio,nitro, amino, mono- or di-(C₁₋₆)alkylamino, mono- ordi-(C₂₋₆)alkenylamino, mono- or di-(C₂₋₆)alkynylamino, formylamino, C₁₋₄alkyl(formyl)amino, C₁₋₄ alkylcarbonylamino, C₁₋₄ alkyl(C₁₋₄alkylcarbonyl)amino, cyano, formyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl, mono- or di-(C₁₋₄)alkylaminocarbonyl,carboxy, C₁₋₄ alkylcarbonyloxy, aryl(C₁₋₄)alkylcarbonyloxy, C₁₋₄alkylsulphinyl, C₁₋₄ alkylsulphonyl or C₁₋₄ alkylsulphonyloxy; R₁ isC₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl in which the alkyl, alkenyl andalkynyl groups are optionally substituted on their terminal carbon atomwith one, two or three halogen atoms, with a cyano group, with a C₁₋₄alkylcarbonyl group, with a C₁₋₄ alkoxycarbonyl group or with a hydroxygroup, or R₁ is alkoxyalkyl, alkylthioalkyl, alkylsulphinylalkyl oralkylsulphonylalkyl in which the total number of carbon atoms is 2 or 3,or R₁ is a straight-chain C₁₋₄ alkoxy group; R₂ is H, C₁₋₄ alkyl, C₁₋₄alkoxymethyl or benzyloxymethyl in which the phenyl ring of the benzylmoiety is optionally substituted with C₁₋₄ alkoxy; R₃ and R₄ areindependently H, C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl provided thatboth are not H and that when both are other than H their combined totalof carbon atoms does not exceed 4, or R₃ and R₄ join with the carbonatom to which they are attached to form a 3 or 4 membered carbocyclicring optionally containing one O, S or N atom and optionally substitutedwith halo or C₁₋₄ alkyl; and R₅ is H, C₁₋₄ alkyl or C₃₋₆ cycloalkyl inwhich the alkyl or cycloalkyl group is optionally substituted with halo,hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, cyano, C₁₋₄ alkylcarbonyloxy,aminocarbonyloxy or mono- or di(C₁₋₄)alkylaminocarbonyloxy,tri(C₁₋₄)alkyl-silyloxy, optionally substituted phenoxy, optionallysubstituted thienyloxy, optionally substituted benzyloxy or optionallysubstituted thienylmethoxy, or R₅ is optionally substituted phenyl,optionally substituted thienyl or optionally substituted benzyl, inwhich the optionally substituted phenyl and thienyl rings of the R₅values are optionally substituted with one, two or three substituentsselected from halo, hydroxy, mercapto, C₁₋₄ alkyl, C₂₋₄, alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C₂₋₄ alkenyloxy, C₂₋₄ alkynyloxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, halo(C₁₋₄)alkylthio,hydroxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄)alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano,thiocyanato, isothiocyanato, nitro, —NR^(m)R^(n), —NHCOR^(m),—NHCONR^(m)R^(n), —CONR^(m)R^(n), —SO₂R^(m), —OSO₂R^(m), —COR^(m),—CR^(m)═NR^(n) or —N═CR^(m)R^(n), in which R^(m) and R^(n) areindependently hydrogen, C₁₋₄ alkyl, halo(C₁₋₄)alkyl, C₁₋₄ alkoxy,halo(C₁₋₄)alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl, the phenyl and benzyl groupsbeing optionally substituted with halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy.10. A compound according to claim 1 wherein one of X and Y is N and theother is CR or both of X and Y are N; Z is H; R is H, halo or cyano; R₁methyl, ethyl, n-propyl, 2,2,2-trifluoromethyl, cyanomethyl,acetylmethyl, methoxycarbonylmethyl, methoxycarbonylethyl,hydroxymethyl, hydroxyethyl, methoxymethyl, methylthiomethyl,ethoxymethyl, 2-methoxyethyl, 2-methylthioethyl, methoxy, ethoxy,n-propoxy or n-butoxy; R₂ is H; R₃ and R₄ are both methyl; and R₅ is H,methyl, hydroxymethyl, methoxymethyl, 1-methoxyethyl,tert-butyldimethylsiloxymethyl, 3-cyanopropyl, 3-methoxypropyl,3-(1,2,4-triazol-1-yl)propyl, 3-methylthiopropyl,3-methanesulphinylpropyl or 3-methanesulphonylpropyl.
 11. A fungicidalcomposition comprising a fungicidally effective amount of a compound offormula (1) as claimed in claim 1 and a suitable carrier or diluenttherefor.
 12. A method of combating or controlling phytopathogenic fungiwhich comprises applying a fungicidally effective amount of a compoundof formula (1) as defined in claim 1 to a plant, to a seed of a plant,to the locus of the plant or seed or to soil or any other plant growthmedium.
 13. A process for the preparation of a compound according toclaim 1, which comprises reacting a compound of the formula (2)

wherein X, Y, and Z have the meanings assigned to them in claim 1, witha compound of the formula (3)

wherein R₁ and R₃ to R₅ have the meanings defined in claim 1 and L is aleaving group, in the presence of a base in a solvent.
 14. A process forthe preparation of a compound according to claim 1, which comprisesreacting a compound of the formula (2)

wherein X, Y, and Z have the meanings assigned to them in claim 1, witha compound of the formula (10a)

wherein R1 has the meaning assigned to it in claim 1, Rd is C₁₋₆ alkyl,and L is a leaving group, to form the compound of formula (11)

which is further reacted with a compound of the formula (5)

in the presence of an activating agent.